mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia

Xie, Luokun; Sun, Fen; Wang, Jixian; Mao, XiaoOu; Xie, Lin; Yang, Shao-Hua; Su, Dong-Ming; Simpkins, James W; Greenberg, David A; Jin, Kunlin

doi:10.4049/jimmunol.1303492

Cited by 175Neuroinflammation and Neurodegeneration MechanismsAcute Ischemic Stroke ManagementTraumatic Brain Injury and Neurovascular Disturbances

mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia

Open access

Xie, Luokun, Sun, Fen, Wang, Jixian, Mao, XiaoOu, Xie, Lin, Yang, Shao-Hua, Su, Dong-Ming, Simpkins, James W +2 more·2014·The Journal of Immunology

DOI 10.4049/jimmunol.1303492PMC PMC4128178

Open this paper in CoChat — free account Open PDF

Abstract

Signaling by the mammalian target of rapamycin (mTOR) plays an important role in the modulation of both innate and adaptive immune responses. However, the role and underlying mechanism of mTOR signaling in poststroke neuroinflammation are largely unexplored. In this study, we injected rapamycin, a mTOR inhibitor, by the intracerebroventricular route 6 h after focal ischemic stroke in rats. We found that rapamycin significantly reduced lesion volume and improved behavioral deficits. Notably, infiltration of γδ T cells and granulocytes, which are detrimental to the ischemic brain, was profoundly reduced after rapamycin treatment, as was the production of proinflammatory cytokines and chemokines by macrophages and microglia. Rapamycin treatment prevented brain macrophage polarization toward the M1 type. In addition, we also found that rapamycin significantly enhanced anti-inflammation activity of regulatory T cells (Tregs), which decreased production of proinflammatory cytokines and chemokines by macrophages and microglia. Depletion of Tregs partially elevated macrophage/microglia-induced neuroinflammation after stroke. Our data suggest that rapamycin can attenuate secondary injury and motor deficits after focal ischemia by enhancing the anti-inflammation activity of Tregs to restrain poststroke neuroinflammation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.4049/jimmunol.1303492

Cites

70 of 70 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

BMP9, MyD88, and mTOR were previously involved in restricting amyloidosis, microglial response to pathogens, and pro-inflammatory microglia.
“which were previously involved in restricting amyloidosis56, microglial response to pathogens57, and pro-inflammatory microglia58”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [58]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269 · cited 2× · see citing works
“According to published M1 and M2 phenotypes (32, 33), we”
Background
Heart Disease and Stroke Statistics—2014 Update
Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Blaha, M. J., Dai, S., Ford, E. S., Fox, C. S., Franco, S., et al. (2013) · Circulation · doi:10.1161/01.cir.0000441139.02102.80 · Cited by 5,207 · see citing works
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840 · cited 1× · see citing works
“According to published M1 and M2 phenotypes (32, 33), we”
Background
The immunology of stroke: from mechanisms to translation
Iadecola, C., & Anrather, J. (2011) · Nature Medicine · doi:10.1038/nm.2399 · Cited by 2,596 · cited 2× · see citing works
“Both damaged/stressed neurons and reactive astrocytes quickly initiate postischemic inflammation, through producing proinflammatory mediators and educating microglia (42, 67, 68).”
Background
mTOR signaling at a glance
Laplante, M., & Sabatini, D. (2009) · Journal of Cell Science · doi:10.1242/jcs.051011 · Cited by 2,317 · cited 1× · see citing works
“under physiological and pathological conditions (7, 8).”
The inhibitory cytokine IL-35 contributes to regulatory T-cell function
Collison, L., Workman, C., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M., Cross, R., Sehy, D., Blumberg, R., & Vignali, D. (2007) · Nature · doi:10.1038/nature06306 · Cited by 2,152 · cited 9× · see citing works
“Three days and 5 d after the initial Ab injection, .50 and 60% of CD4+Foxp3+ Tregs in the blood were depleted, respectively (Fig.”
BackgroundInfluential
A Semiautomated Method for Measuring Brain Infarct Volume
Swanson, R., Morton, M. T., Tsao-Wu, G., Savalos, R. A., Davidson, C., & Sharp, F. (1990) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1038/jcbfm.1990.47 · Cited by 1,727 · cited 1× · see citing works
“Lesion area was measured by a blinded observer, as described previously (14).”
Method
Inflammatory mechanisms in ischemic stroke: role of inflammatory cells
Jin, R., Yang, G., & Li, G. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.1109766 · Cited by 1,521 · cited 2× · see citing works
“Poststroke neuroinflammation plays critical roles in the pathophysiology of ischemic stroke, which is characterized by peripheral leukocyte influx into the cerebral parenchyma, activation of endogenous microglia, and release of proinflammatory mediators (5, 39).”
Background
Microglia/Macrophage Polarization Dynamics Reveal Novel Mechanism of Injury Expansion After Focal Cerebral Ischemia
Hu, X.-M., Li, P.-Y., Guo, Y., Wang, H., Leak, R., Chen, S., Gao, Y.-Q., & Chen, J. (2012) · Stroke · doi:10.1161/strokeaha.112.659656 · Cited by 1,445 · cited 1× · see citing works
“Previous studies have documented the proinflammatory (M1) and anti-inflammatory (M2) macrophages in the postischemic brains (65, 66).”
Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3+ T Regulatory Cells
Thornton, A. M., Korty, P. E., Tran, D. Q., Wohlfert, E. A., Murray, P. E., Belkaid, Y., & Shevach, E. M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904028 · Cited by 1,382 · cited 1× · see citing works
“Splenic Tregs contain mainly natural Tregs (38).”
mTOR differentially regulates effector and regulatory T cell lineage commitment
Delgoffe, G. M., Kole, T., Zheng, Y., Zarek, P. E., Matthews, K., Xiao, B., Worley, P., Kozma, S., & Powell, J. (2009) · Immunity · doi:10.1016/j.immuni.2009.04.014 · Cited by 1,293 · see citing works
The inflammatory response in stroke.
Wang, Q., Tang, X.-N., & Yenari, M. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.11.014 · Cited by 1,195 · cited 1× · see citing works
“the ischemic brain and may potentiate injury by secreting deleterious neuroinflammatory mediators (40).”
Background
Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat
Jin, K., Minami, M., Lan, J., Mao, X., Batteur, S., Simon, R., & Greenberg, D. A. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.081011098 · Cited by 1,117 · cited 1× · see citing works
“Transient focal cerebral ischemia was induced using the suture occlusion technique, as previously described (13).”
MethodSelf-citation
Temporal and Spatial Dynamics of Cerebral Immune Cell Accumulation in Stroke
Gelderblom, M., Leypoldt, F., Steinbach, K., Behrens, D., Choe, C.-U., Siler, D. A., Arumugam, T. V., Orthey, E., Gerloff, C., Tolosa, E., et al. (2009) · Stroke · doi:10.1161/strokeaha.108.534503 · Cited by 1,066 · cited 1× · see citing works
“Previous studies have indicated that leukocyte accumulation, including T cells, B cells, granulocytes, and monocytes, starts on day 1 and peaks on day 3 after onset of ischemia (16, 27).”
Background
Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke
Liesz, A., Suri-Payer, E., Veltkamp, C., Doerr, H., Sommer, C., Rivest, S., Giese, T., & Veltkamp, R. (2009) · Nature Medicine · doi:10.1038/nm.1927 · Cited by 1,059 · cited 2× · see citing works
“Tregs are able to protect ischemic brain damage (37).”
Background
CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative
Ghiringhelli, F., Larmonier, N., Schmitt, E., Parcellier, A., Cathelin, D., Garrido, C., Chauffert, B., Solary, É., Bonnotte, B., & Martin, F. (2004) · European Journal of Immunology · doi:10.1002/eji.200324181 · Cited by 878 · cited 1× · see citing works
“To deplete Tregs in vivo, anti-rat CD25 mAb (OX-39; AbD Serotec) was used according to previous literature with modifications (17, 18).”
Method
Immunoregulatory functions of mTOR inhibition
Thomson, A. W., Turnquist, H. R., & Raimondi, G. (2009) · Nature reviews. Immunology · doi:10.1038/nri2546 · Cited by 849 · cited 2× · see citing works
“However, rapamycin itself might inhibit IL-10 mRNA and protein in Tregs, as in macrophages (9).”
Background
Tumor necrosis factor-alpha expression in ischemic neurons.
Liu, T., Clark, R., Mcdonnell, P., Young, P., White, R. F., Barone, F., & Feuerstein, G. (1994) · Stroke · doi:10.1161/01.str.25.7.1481 · Cited by 782 · see citing works
Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4 + CD25 + regulatory T cell proliferation
Ghiringhelli, F., Puig, P. E., Roux, S., Parcellier, A., Schmitt, E., Solary, É., Kroemer, G., Martin, F., Chauffert, B., & Zitvogel, L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050463 · Cited by 776 · cited 1× · see citing works
“To deplete Tregs in vivo, anti-rat CD25 mAb (OX-39; AbD Serotec) was used according to previous literature with modifications (17, 18).”
Method
The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells
Haxhinasto, S., Mathis, D., & Benoist, C. (2008) · Journal of Experimental Medicine · doi:10.1084/jem.20071477 · Cited by 775 · see citing works
Inflammatory Cytokines in Experimental and Human Stroke
Lambertsen, K., Biber, K., & Finsen, B. (2012) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1038/jcbfm.2012.88 · Cited by 730 · cited 1× · see citing works
“Both damaged/stressed neurons and reactive astrocytes quickly initiate postischemic inflammation, through producing proinflammatory mediators and educating microglia (42, 67, 68).”
Background
Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice
Perego, C., Fumagalli, S., & Simoni, M. G. D. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-174 · Cited by 504 · cited 1× · see citing works
“Previous studies have documented the proinflammatory (M1) and anti-inflammatory (M2) macrophages in the postischemic brains (65, 66).”
Rapamycin-Conditioned Dendritic Cells Are Poor Stimulators of Allogeneic CD4+ T Cells, but Enrich for Antigen-Specific Foxp3+ T Regulatory Cells and Promote Organ Transplant Tolerance
Turnquist, H. R., Raimondi, G., Zahorchak, A. F., Fischer, R. T., Wang, Z., & Thomson, A. W. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.11.7018 · Cited by 442 · cited 1× · see citing works
“It has been reported that rapamycin-treated endothelial cells and dendritic cells may promote Treg activity in ischemic brains (63, 64).”
Background
Interleukin-10 in the brain.
Strle, K., Zhou, J.-H., Shen, W. H., Broussard, S., Johnson, R. W., Freund, G., Dantzer, R., & Kelley, K. (2001) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v21.i5.20 · Cited by 408 · see citing works
Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation.
Kleinschnitz, C., Schwab, N., Kraft, P., Hagedorn, I., Dreykluft, A., Schwarz, T. J., Austinat, M., Nieswandt, B., Wiendl, H., & Stoll, G. (2010) · Blood · doi:10.1182/blood-2009-10-249078 · Cited by 361 · cited 1× · see citing works
“T lymphocytes also influence the ischemic lesion independently of Ag specificity and costimulatory molecules (41), although there are conflicting data (42).”
Background
Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.
Kleinschnitz, C., Kraft, P., Dreykluft, A., Hagedorn, I., Göbel, K., Schuhmann, M., Langhauser, F., Helluy, X., Schwarz, T. J., Bittner, S., et al. (2013) · Blood · doi:10.1182/blood-2012-04-426734 · Cited by 360 · cited 1× · see citing works
“However, their protective role still needs further confirmation because controversies emerge (43, 44).”
Background
Interleukin-1 beta mRNA expression in ischemic rat cortex.
Liu, T., Mcdonnell, P., Young, P., White, R. F., Sirén, A., Hallenbeck, J., Barone, F., & Feurestein, G. (1993) · Stroke · doi:10.1161/01.str.24.11.1746 · Cited by 324 · see citing works
Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat.
Kim, J. S., Gautam, S., Chopp, M., Zaloga, C., Jones, M. L., Ward, P., & Welch, K. (1995) · Journal of Neuroimmunology · doi:10.1016/0165-5728(94)00138-e · Cited by 299 · see citing works
Leukocyte Recruitment and Ischemic Brain Injury
Yilmaz, G., & Granger, D. (2009) · Neuromolecular medicine · doi:10.1007/s12017-009-8074-1 · Cited by 285 · cited 1× · see citing works
“Poststroke neuroinflammation plays critical roles in the pathophysiology of ischemic stroke, which is characterized by peripheral leukocyte influx into the cerebral parenchyma, activation of endogenous microglia, and release of proinflammatory mediators (5, 39).”
Background
Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia
Carloni, S., Girelli, S., Scopa, C., Buonocore, G., Longini, M., & Balduini, W. (2010) · Autophagy · doi:10.4161/auto.6.3.11261 · Cited by 269 · cited 1× · see citing works
“neonatal rats (11) and improves neuron viability in an in vitro”
Background
Concomitant cortical expression of TNF-α and IL-1β mRNAs follows early response gene expression in transient focal ischemia
Wang, X.-K., Yue, T., Barone, F., White, R. F., Gagnon, R., & Feuerstein, G. (1994) · Molecular and Chemical Neuropathology · doi:10.1007/bf02815404 · Cited by 262 · see citing works
Monocyte chemoattractant protein-1 messenger RNA expression in rat ischemic cortex.
Wang, X.-K., Yue, T., Barone, F., & Feuerstein, G. (1995) · Stroke · doi:10.1161/01.str.26.4.661 · Cited by 203 · see citing works
The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes
Lisi, L., Navarra, P., Feinstein, D., & Russo, C. D. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-1 · Cited by 194 · cited 1× · see citing works
“Rapamycin protects neurons after stroke (12, 69) and inhibits reactive astrocytes (70, 71), thus probably preventing the onset of acute neuroinflammation.”
Background
Mechanism of action of rapamycin: new insights into the regulation of G1-phase progression in eukaryotic cells.
Wiederrecht, G., Sabers, C. J., Brunn, G., Martin, M. M., Dumont, F., & Abraham, R. (1995) · Progress in cell cycle research · doi:10.1007/978-1-4615-1809-9_5 · Cited by 191 · cited 1× · see citing works
“under physiological and pathological conditions (7, 8).”
Rapamycin unbalances the polarization of human macrophages to M1
Mercalli, A., Calavita, I., Dugnani, E., Citro, A., Cantarelli, E., Nano, R., Melzi, R., Maffi, P., Secchi, A., Sordi, V., et al. (2013) · Immunology · doi:10.1111/imm.12126 · Cited by 189 · see citing works
Treatment of Acute Ischemic Stroke.
Siket, M. (2016) · Emergency medicine clinics of North America · doi:10.1016/j.emc.2016.06.009 · Cited by 184 · cited 1× · see citing works
“tissue plasminogen activator remains the only treatment proven to improve clinical outcome of patients with acute ischemic stroke (2).”
Background
Cytokines and cell adhesion molecules in cerebral ischemia: experimental bases and therapeutic perspectives.
Pantoni, L., Sarti, C., & Inzitari, D. (1998) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/01.atv.18.4.503 · Cited by 173 · cited 1× · see citing works
“Importantly, the temporal profile of chemokines such as CCL2 and CCL3 is in line with that of leukocyte accumulation in the ischemic brain parenchyma (26).”
Background
The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord
Codeluppi, S., Svensson, C., Hefferan, M., Valencia, F., Silldorff, M. D., Oshiro, M., Marsala, M., & Pasquale, E. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.4103-08.2009 · Cited by 168 · cited 1× · see citing works
“Rapamycin protects neurons after stroke (12, 69) and inhibits reactive astrocytes (70, 71), thus probably preventing the onset of acute neuroinflammation.”
Background
Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds
Lança, T., Costa, M. F., Gonçalves-Sousa, N., Rei, M., Grosso, A., Penido, C., & Silva-Santos, B. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1300434 · Cited by 166 · see citing works
Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells.
Shin, H., Baker, J., Leveson-Gower, D., Smith, A. T., Sega, E. I., & Negrin, R. (2011) · Blood · doi:10.1182/blood-2010-10-313684 · Cited by 160 · see citing works
Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke.
Frenkel, D., Huang, Z., Maron, R., Koldzic, D. N., Moskowitz, M., & Weiner, H. (2005) · Journal of Neurological Sciences · doi:10.1016/j.jns.2005.03.022 · Cited by 141 · see citing works
TSC1 regulates the balance between effector and regulatory T cells.
Park, Y., Jin, H.-S., Lopez, J. M., Elly, C., Kim, G., Murai, M., Kronenberg, M., & Liu, Y.-C. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69751 · Cited by 132 · see citing works
Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability
Lee, J., Lydon, J., & Kim, C. H. (2012) · European Journal of Immunology · doi:10.1002/eji.201142317 · Cited by 129 · see citing works
Inflammation-Driven Reprogramming of CD4+Foxp3+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo
Yurchenko, E., Shio, M. T., Huang, T. C. T., Martins, M. D. S., Szyf, M., Levings, M., Olivier, M., & Piccirillo, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035572 · Cited by 127 · cited 10× · see citing works
“Three days and 5 d after the initial Ab injection, .50 and 60% of CD4+Foxp3+ Tregs in the blood were depleted, respectively (Fig.”
BackgroundInfluential
IL‐2 induces in vivo suppression by CD4+CD25+Foxp3+ regulatory T cells
Brandenburg, S., Takahashi, T., Rosa, M. D. L., Janke, M., Karsten, G., Muzzulini, T., Orinska, Z., Bulfone-Paus, S., & Scheffold, A. (2008) · European Journal of Immunology · doi:10.1002/eji.200737791 · Cited by 127 · see citing works
CD4+FoxP3+ regulatory T-cells in cerebral ischemic stroke
Ren, X., Akiyoshi, K., Vandenbark, A., Hurn, P., & Offner, H. (2010) · Metabolic brain disease · doi:10.1007/s11011-010-9226-6 · Cited by 121 · cited 1× · see citing works
“However, their protective role still needs further confirmation because controversies emerge (43, 44).”
Background
The Production of IL-10 by Human Regulatory T Cells Is Enhanced by IL-2 through a STAT5-Responsive Intronic Enhancer in the IL-10 Locus
Tsuji‐Takayama, K., Suzuki, M., Yamamoto, M., Harashima, A., Okochi, A., Otani, T., Inoue, T., Sugimoto, A., Toraya, T., Takeuchi, M., et al. (2008) · Journal of Immunology · doi:10.4049/jimmunol.181.6.3897 · Cited by 112 · see citing works
Induced Regulatory T Cells Promote Tolerance When Stabilized by Rapamycin and IL-2 In Vivo
Zhang, P., Tey, S.-K., Koyama, M., Kuns, R. D., Olver, S., Lineburg, K., Lor, M., Teal, B. E., Raffelt, N. C., Raju, J., et al. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1301181 · Cited by 110 · cited 10× · see citing works
“Three days and 5 d after the initial Ab injection, .50 and 60% of CD4+Foxp3+ Tregs in the blood were depleted, respectively (Fig.”
BackgroundInfluential
Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats
Hill, J. J., Jin, K., Mao, X., Xie, L., & Greenberg, D. A. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1205697109 · Cited by 99 · cited 1× · see citing works
“Western blot was performed using the protocol as previously described (19).”
MethodSelf-citation
Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage
Viscomi, M. T., D'Amelio, M., Cavallucci, V., Latini, L., Bisicchia, E., Nazio, F., Fanelli, F., Maccarrone, M., Moreno, S., Cecconi, F., et al. (2012) · Autophagy · doi:10.4161/auto.8.2.18599 · Cited by 99 · see citing works
Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats
Chauhan, A., Sharma, U., Jagannathan, N. R., Reeta, K. H., & Gupta, Y. K. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.08.035 · Cited by 98 · cited 2× · see citing works
“chemia ameliorated motor impairment in adult rats (10) and in”
Background
Expression of transforming growth factor-?1 and interleukin-1? mRNA in rat brain following transient forebrain ischemia
Wie�ner, C., Gehrmann, J., Lindholm, D., T�pper, R., Kreutzberg, G. W., & Hossmann, K. A. (1993) · Acta Neuropathologica · doi:10.1007/bf00228578 · Cited by 94 · see citing works
Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: A critical review of the literature
Sughrue, M., Mehra, A., Connolly, E., & D'ambrosio, A. (2004) · Inflammation Research · doi:10.1007/s00011-004-1282-0 · Cited by 88 · cited 1× · see citing works
“However, several therapeutic trials targeting neuroinflammatory response have failed to show clinical benefit (6).”
Background
Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells.
Wang, C., Yi, T., Qin, L.-F., Maldonado, R. A., von Andrian, U. V., Kulkarni, S., Tellides, G., & Pober, J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66204 · Cited by 71 · cited 1× · see citing works
“It has been reported that rapamycin-treated endothelial cells and dendritic cells may promote Treg activity in ischemic brains (63, 64).”
Background
An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tPA for ischemic stroke in rodents
Wang, Y.-M., Zhang, Z.-G., Chow, N., Davis, T., Griffin, J., Chopp, M., & Zlokovic, B. (2012) · Stroke · doi:10.1161/strokeaha.112.658997 · Cited by 70 · see citing works
Expanding human T regulatory cells with the mTOR-inhibitor rapamycin.
Battaglia, M., Stabilini, A., & Tresoldi, E. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-430-8_17 · Cited by 66 · see citing works
Regulatory T Cells Require Mammalian Target of Rapamycin Signaling To Maintain Both Homeostasis and Alloantigen-Driven Proliferation in Lymphocyte-Replete Mice
Wang, Y., Camirand, G., Lin, Y., Froicu, M., Deng, S.-Y., Shlomchik, W. D., Lakkis, F. G., & Rothstein, D. (2011) · Journal of Immunology · doi:10.4049/jimmunol.0903805 · Cited by 64 · see citing works
Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-alpha expression in macrophages by reducing IL-10 expression
Baker, A. K., Wang, R.-P., Mackman, N., & Luyendyk, J. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.04.011 · Cited by 56 · cited 1× · see citing works
“Our data are generally consistent with previous publications that demonstrated that rapamycin enhances proinflammatory activity of macrophages (28, 29).”
Result
Rapamycin Treatment Improves Neuron Viability in an In Vitro Model of Stroke
Fletcher, L., Evans, T., Watts, L., Jimenez, D., & Digicaylioglu, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068281 · Cited by 54 · cited 1× · see citing works
“Rapamycin protects neurons after stroke (12, 69) and inhibits reactive astrocytes (70, 71), thus probably preventing the onset of acute neuroinflammation.”
Background
Policing the Police: Astrocytes Modulate Microglial Activation
Shih, A. Y., Fernandes, H., Choi, F. Y., Kozoriz, M. G., Liu, Y.-R., Li, P., Cowan, C., & Klegeris, A. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0936-06.2006 · Cited by 49 · cited 1× · see citing works
“Both damaged/stressed neurons and reactive astrocytes quickly initiate postischemic inflammation, through producing proinflammatory mediators and educating microglia (42, 67, 68).”
Background
γδ T cells in Experimental Autoimmune Encephalomyelitis: Early Trafficking Events and Cytokine Requirements
Wohler, J., Smith, S. S., Zinn, K. R., Bullard, D., & Barnum, S. (2009) · European Journal of Immunology · doi:10.1002/eji.200839176 · Cited by 42 · see citing works
Interpreting Mammalian Target of Rapamycin and Cell Growth Inhibition in a Genetically Engineered Mouse Model of Nf1 -Deficient Astrocytes
Banerjee, S., Gianino, S. M., Gao, F., Christians, U., & Gutmann, D. H. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0654 · Cited by 38 · cited 1× · see citing works
“Rapamycin can cross the blood brain barrier into the brain parenchyma even in the steady state (72).”
Background
IL-2 activation of STAT5 enhances production of IL-10 from human cytotoxic regulatory T cells, HOZOT.
Tsuji‐Takayama, K., Suzuki, M., Yamamoto, M., Harashima, A., Okochi, A., Otani, T., Inoue, T., Sugimoto, A., Motoda, R., Yamasaki, F., et al. (2008) · Experimental Hematology · doi:10.1016/j.exphem.2007.09.010 · Cited by 36 · see citing works
Involvement of CC chemokines in γδ T lymphocyte trafficking during allergic inflammation: the role of CCL2/CCR2 pathway
Penido, C., Costa, M. F. D. S., Souza, M. C., Costa, K. A., Candea, A., Benjamim, C., & Henriques, M. D. G. M. O. (2008) · International Immunology · doi:10.1093/intimm/dxm128 · Cited by 36 · see citing works
Rapamycin induces transforming growth factor-β production by lymphocytes
Dodge, I., Demirci, G., Strom, T., & Li, X.-C. (2000) · Transplantation · doi:10.1097/00007890-200010150-00020 · Cited by 35 · see citing works
Combined Administration of a Mutant TGF-β1/Fc and Rapamycin Promotes Induction of Regulatory T Cells and Islet Allograft Tolerance
Zhang, W., Zhang, D., Shen, M., Liu, Y., Tian, Y., Thomson, A. W., Lee, W. P. A., & Zheng, X. X. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000769 · Cited by 25 · see citing works
Effect of rapamycin and interleukin-2 on regulatory CD4+CD25+Foxp3+ T cells in mice after allogenic corneal transplantation.
Wang, X.-Y., Wang, W., Xu, J., & Le, Q.-H. (2013) · Transplantation Proceedings · doi:10.1016/j.transproceed.2012.06.064 · Cited by 19
Intravenous recombinant tissue-type plasminogen activator in the extended time window and the US Food and Drug Administration: confused about the time.
Wechsler, L., & Jovin, T. (2012) · Stroke · doi:10.1161/strokeaha.112.670554 · Cited by 19
Effect of a contralateral lesion on neurological recovery from stroke in rats
Sun, F., Xie, L., Mao, X., Hill, J. J., Greenberg, D. A., & Jin, K. (2012) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-2012-120254 · Cited by 15 · cited 1× · see citing works
“The neurobehavioral tests, including beam balance test, limb placing test, and elevated body swing test, were performed according to our previous publications (15).”
MethodSelf-citation
Pretreatment of rapamycin before allogenic corneal transplant promotes graft survival through increasing CD4(+)CD25(+)Foxp3(+) regulatory T cells.
Wang, X., Wang, W.-T., Xu, J.-J., Hong, J., & Le, Q. (2012) · Experimental and Clinical Transplantation · doi:10.6002/ect.2012.0025 · Cited by 11 · cited 1× · see citing works
“Researchers have observed rapamycin-induced TGF-b production by lymphocytes and infiltrated Tregs in previous studies (61, 62).”
Background

Flagged first, then by citations

6 of the 76 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

[16]Shichita T Sugiyama Y Ooboshi H Sugimori H Nakagawa R Takada I Iwaki T Okada Y Iida M Cua DJ Iwakura Y Yoshimura A Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury Nature medicine 2009 15 946 950 19648929
[28]Shichita T Sugiyama Y Ooboshi H Sugimori H Nakagawa R Takada I Iwaki T Okada Y Iida M Cua DJ Iwakura Y Yoshimura A Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury Nat Med 2009 15 946 950 19648929
[46]Wohler JE Smith SS Zinn KR Bullard DC Barnum SR Gammadelta T cells in EAE: early trafficking events and cytokine requirements Eur J Immunol 2009 39 1516 1526 19384874 PMC2837942
[47]Lakhan SE Kirchgessner A Hofer M Inflammatory mechanisms in ischemic stroke: therapeutic approaches Journal of translational medicine 2009 7 97 19919699 PMC2780998
[62]Thomson AW Turnquist HR Raimondi G Immunoregulatory functions of mTOR inhibition Nat Rev Immunol 2009 9 324 337 19390566 PMC2847476

Sorted by citations

Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies
Jurcău, A., & Simion, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010014 · Cited by 515 · see citing works
“Treg depletion led to increased infarct sizes in three studies [288–290], and one study found a reduced infarct size in Treg-deficient mice [111], while other studies could not detect any influence on infarct size [111,291].”
Result
Microglia: Agents of the CNS Pro-Inflammatory Response
Rodríguez-Gómez, J. A., Kavanagh, E., Engskog-Vlachos, P., Engskog, M. K. R., Herrera, A. J., Espinosa-Oliva, A. M., Joseph, B., Hajji, N., Venero, J. L., & Burguillos, M. A. (2020) · Cells · doi:10.3390/cells9071717 · Cited by 365 · see citing works
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357 · see citing works
Immune cell regulation of glia during CNS injury and disease
Greenhalgh, A. D., David, S., & Bennett, F. C. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0263-9 · Cited by 398 · see citing works
Modulators of microglia activation and polarization in ischemic stroke
Jiang, C., Wu, W., Deng, Y.-H., & Ge, J.-W. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11003 · Cited by 355 · see citing works
“…was observed to recruit cd8 + γδ T cells to the ischemic brain, which was identified to be the primary factor aggravating brain infarction (32,33). in fact, besides ischemic stroke, M1 microglia activation occurs in multiple other neurological diseases; for example, in an RD1 mouse model…”
Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway
Xu, X., Gao, W., Li, L., Hao, J.-H., Yang, B., Wang, T., Li, L., Bai, X.-S., Li, F., Ren, H., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02174-3 · Cited by 253 · see citing works
Self-citation
The Involvement and Therapy Target of Immune Cells After Ischemic Stroke
Jian, Z., Liu, R., Zhu, X., Smerin, D., Zhong, Y., Gu, L., Fang, W., & Xiong, X. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02167 · Cited by 232 · see citing works
“Inhibition of mTORC1 pathway by everolimus reduced microglia polarizing to pro-inflammatory M1 phenotype, alleviated secondary injury and improved motor functions, which directly acts of microglia and macrophages (146, 147) (Table 3).”
Background
Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice
Wang, Y., Tian, M., Tan, J.-Y., Pei, X., Lu, C., Xin, Y., Deng, S.-X., Zhao, F., Gao, Y.-Q., & Gong, Y. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02438-6 · Cited by 205 · see citing works
“AMPK activation (phosphorylation of α subunit at thr172) is suggested to alleviate inflammation and promote microglial/macrophage polarization to the M2-phenotype [30, 31].”
Background
Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia
Nguyen, H. M., Grössinger, E. M., Horiuchi, M., Davis, K. W., Jin, L., Maezawa, I., & Wulff, H. (2017) · Glia · doi:10.1002/glia.23078 · Cited by 178 · see citing works
“Resting, or more appropriately termed “surveillant” microglia continuously survey their environment with fine cellular processes (Nimmerjahn et al., 2005).”
BackgroundMethod
Functional Role of Regulatory Lymphocytes in Stroke
Liesz, A., Hu, X., Kleinschnitz, C., & Offner, H. (2015) · Stroke · doi:10.1161/strokeaha.114.008608 · Cited by 186 · see citing works
Microthrombus‐Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke
Lü, Y., Li, C., Chen, Q., Liu, P., Guo, Q., Zhang, Y., Chen, X., Zhang, Y., Zhou, W., Liang, D., et al. (2019) · Advanced Materials · doi:10.1002/adma.201808361 · Cited by 185 · see citing works
Paradoxical changes in innate immunity in aging: recent progress and new directions
Montgomery, R. R., & Shaw, A. C. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.5mr0315-104r · Cited by 147 · see citing works
“[40] and age-associated cardiac dysfunction [41].”
Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms
Alyu, F., & Dikmen, M. (2016) · Acta Neuropsychiatrica · doi:10.1017/neu.2016.47 · Cited by 147 · see citing works
“In addition, reduction of microglia-mediated neuroinflammation has been suggested to involve mTOR pathway (100).”
Background
mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type
Li, D., Wang, C.-J., Yao, Y., Chen, L., Liu, G., Zhang, R., Liu, Q., Shi, F.-D., & Hao, J. (2016) · The FASEB Journal · doi:10.1096/fj.201600495r · Cited by 147 · see citing works
The potential role of necroptosis in inflammaging and aging
Royce, G. H., Brown‐Borg, H. M., & Deepa, S. S. (2019) · GeroScience · doi:10.1007/s11357-019-00131-w · Cited by 135 · see citing works
Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches
Shekhar, S., Cunningham, M. W., Pabbidi, M. R., Wang, S.-X., Booz, G., & Fan, F. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.06.028 · Cited by 125 · see citing works
“• Mammalian target of rapamycin (mTOR) pathway is a known regulator of immune responses, and inhibition of the mTORC1 pathway pharmacologically or genetically prevents microglial polarization toward the M1 pro-inflammatory phenotype in the context of ischemic stroke (Li et al., 2016; Xie et al., 2014).”
Rapamycin increases neuronal survival, reduces inflammation and astrocyte proliferation after spinal cord injury.
Goldshmit, Y., Kanner, S., Zacs, M., Frisca, F., Pinto, A., Currie, P., & Pinkas-Kramarski, R. (2015) · Molecular and cellular neurosciences · doi:10.1016/j.mcn.2015.04.006 · Cited by 121 · see citing works
Peripheral immune cells infiltrate into sites of secondary neurodegeneration after ischemic stroke
Jones, K., Maltby, S., Plank, M. W., Kluge, M. G., Nilsson, M., Foster, P. S., & Walker, F. R. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.09.006 · Cited by 127 · see citing works
Dynamics of T cell responses after stroke.
Gill, D., & Veltkamp, R. (2016) · Current opinion in pharmacology (Print) · doi:10.1016/j.coph.2015.09.009 · Cited by 116 · see citing works
“Indeed, the therapeutic benefit of harnessing Treg mediated protection has been explored with rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) signalling [34].”
Background
A New Model of Cuprizone-Mediated Demyelination/Remyelination
Sachs, H. H., Bercury, K., Popescu, D., Narayanan, S., & Macklin, W. B. (2014) · ASN Neuro · doi:10.1177/1759091414551955 · Cited by 115 · see citing works
Amplification of Regulatory T Cells Using a CD28 Superagonist Reduces Brain Damage After Ischemic Stroke in Mice
Na, S., Mracsko, E., Liesz, A., Hünig, T., & Veltkamp, R. (2015) · Stroke · doi:10.1161/strokeaha.114.007756 · Cited by 108 · see citing works
“Compared with direct adoptive Treg cell transfer, which is technically demanding and time consuming,(10,11) pharmacological amplification of endogenous Treg may be more feasible in acute stroke.(11,12) The superagonistic CD28 monoclonal antibody (CD28SA) activates T cells without T cell receptor engagement.”
BackgroundResult
Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-γ gene expression in acute experimental traumatic brain injury
Krämer, T. J., Hack, N., Brühl, T. J., Menzel, L., Hummel, R., Griemert, E., Klein, M., Thal, S., Bopp, T., & Schäfer, M. K. E. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1550-0 · Cited by 99 · see citing works
Anti-inflammatory treatments for stroke: from bench to bedside
Drieu, A., Levard, D., Vivien, D., & Rubio, M. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418789854 · Cited by 101 · see citing works
Experimental ischemic stroke induces long-term T cell activation in the brain
Xie, L.-K., Li, W.-J., Hersh, J., Liu, R., & Yang, S.-H. (2018) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x18792372 · Cited by 91 · see citing works
“Isolation of immune cells from the brains and spleens was performed at day 3 or one month post-MCAO as published earlier.(27,29) Briefly, mouse cerebral hemispheres and spleens were cut into 1 mm(3) pieces before digestion for 45min at 37 C with digestion buffer (RPMI 1640 medium supplemented with 10% fetal bovine ser…”
MethodSelf-citation
The role of autophagy in pro‐inflammatory responses of microglia activation via mitochondrial reactive oxygen species in vitro
Ye, J., Jiang, Z., Chen, X., Liu, M., Li, J., & Liu, N. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14042 · Cited by 92 · see citing works
“Also, rapamycin has been found as a direct inducer of M1 polarization of macrophages and microglia, it also strongly enhances Treg activity, which in turn restrains the inflammatory response of macrophages and microglia (Xie et al. 2014).”
Background
Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy
Beccari, S., Sierra-Torre, V., Valero, J., Pereira-Iglesias, M., García-Zaballa, M., Soria, F. N., De Las Heras-Garcia, L., Carretero-Guillen, A., Capetillo-Zarate, E., Domercq, M., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2165313 · Cited by 89 · see citing works
“systemic administration of rapamycin may modulate peripheral immune cell inflammatory profile and activities, including their migration to the CNS, indirectly affecting microglial functions [66].”
Background
Regulatory T Cells in Post-stroke Immune Homeostasis
Liesz, A., & Kleinschnitz, C. (2016) · Translational Stroke Research · doi:10.1007/s12975-016-0465-7 · Cited by 97 · see citing works
“exacerbation of stroke outcome after Treg depletion also observed an associated increase in neuroinflammatory biomarkers [17, 21, 38].”
Influential
Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria
Gabandé‐Rodríguez, E., Heras, M. M. G. D. L., & Mittelbrunn, M. (2019) · Cells · doi:10.3390/cells9010082 · Cited by 96 · see citing works
Interleukin-4 Ameliorates the Functional Recovery of Intracerebral Hemorrhage Through the Alternative Activation of Microglia/Macrophage
Yang, J., Ding, S., Huang, W., Hu, J., Huang, S., Zhang, Y., & Zhuge, Q. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00061 · Cited by 87 · see citing works
“For M1 makers, we found that the expression level of iNOS (P < 0.01; n = 6) was significantly increased at 1 day post ICH (Figure 1A), while those of IL-1β (P < 0.05; n = 6), TNF-α (P < 0.05; n = 6), and IL-6 (P < 0.01; n = 6) were increased at 3 h post ICH (Figures 1B–”
BackgroundInfluential
Post-stroke DHA Treatment Protects Against Acute Ischemic Brain Injury by Skewing Macrophage Polarity Toward the M2 Phenotype
Cai, W., Liu, S., Hu, M.-Y., Sun, X.-B., Qiu, W., Zheng, S.-G., Hu, X.-M., & Lu, Z.-Q. (2018) · Translational Stroke Research · doi:10.1007/s12975-018-0662-7 · Cited by 79 · see citing works
Targeting brain-peripheral immune responses for secondary brain injury after ischemic and hemorrhagic stroke
Duan, M., Xu, Y., Li, Y., Feng, H., & Chen, Y. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03101-y · Cited by 82 · see citing works
“In terms of neuroprotective effects, researchers have demonstrated in stroke models that the mTOR inhibitor rapamycin protects neurons through the anti-inflammatory effects of Tregs [295, 296].”
Background
Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats
Wu, M.-L., Zhang, H.-D., Kai, J.-J., Zhu, F., Dong, J.-Y., Xu, Z.-W., Wong, M., & Zeng, L.-H. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.507 · Cited by 73 · see citing works
“Currently, systemic thrombolysis with recombinant intravenous tissue plasminogen activator (rtPA) remains a frequently used therapy which can improve clinical outcome of patients with acute ischemic stroke.(3,4) However, rtPA has an increased risk of hemorrhage beyond a few hours of poststroke, and only less than 4% o…”
Background
Sestrin2, as a negative feedback regulator of mTOR, provides neuroprotection by activation AMPK phosphorylation in neonatal hypoxic-ischemic encephalopathy in rat pups
Shi, X.-D., Xu, L., Doycheva, D., Tang, J.-P., Yan, M., & Zhang, J. H. (2017) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x16656201 · Cited by 72 · see citing works
Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experimental brain ischemia
He, T., Li, W., Song, Y., Li, Z., Tang, Y., Zhang, Z., & Yang, G. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01987-y · Cited by 80 · see citing works
“It has been shown that blockade of mTORC1 signaling enabled microglia to polarize toward the M2 phenotype to exert anti-inflammatory effects after stroke [47, 48].”
Background
Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments
Krystal, J., Kaye, A. P., Jefferson, S., Girgenti, M., Wilkinson, S. T., Sanacora, G., & Esterlis, I. (2023) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2305772120 · Cited by 69 · see citing works
Perivascular adipose tissue, inflammation and insulin resistance: link to vascular dysfunction and cardiovascular disease
Lastra, G., & Manrique, C. M. (2015) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2015-0010 · Cited by 70 · see citing works
“Loss of Tregs function has been shown to result in M1 macrophage polarization and inflammation [51, 52].”
Background
The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System
Wo, J., Zhang, F., Li, Z., Sun, C., Zhang, W.-C., & Sun, G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.580304 · Cited by 80 · see citing works
“Hence, gd T cells and IL-17 should be considered potential therapeutic targets to decrease secondary inflammation after ischemic brain injury (105, 106).”
Background
Host Resistance and Immune Aging
Bandaranayake, T., & Shaw, A. C. (2016) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2016.02.007 · Cited by 85 · see citing works
Rapamycin inhibits oxidative/nitrosative stress and enhances angiogenesis in high glucose-treated human umbilical vein endothelial cells: Role of autophagy.
Rezabakhsh, A., Ahmadi, M., Khaksar, M., Montaseri, A., Malekinejad, H., Rahbarghazi, R., & Garjani, A. (2017) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2017.07.044 · Cited by 67 · see citing works
Positive effects of intermittent fasting in ischemic stroke
Fann, D., Ng, G., Poh, L., & Arumugam, T. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.01.014 · Cited by 66 · see citing works
“…cell adhesion molecules (E-selectin, ICAM-1 and VCAM-1) in rodent brains following cerebral ischemia (Aljada et al., 2006; Harari and Liao, 2010; Howard et al., 1998; Lee et al., 2015; Nam et al., 2009; Sanacora et al., 2014; Supanc et al., n.d.; Xing and Remick, 2007; Zampetaki et al., 2004).”
The Effect of A2A Receptor Antagonist on Microglial Activation in Experimental Glaucoma.
Liu, X., Huang, P., Wang, J., Yang, Z., Huang, S., Luo, X.-D., Qi, J., Shen, X., & Zhong, Y. (2016) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.15-18024 · Cited by 55 · see citing works
Self-citation
CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia
Boddaert, J., Bielen, K., ’s Jongers, B., Manocha, E., Yperzeele, L., Cras, P., Pirici, D., & Kumar-Singh, S. (2018) · PLOS ONE · doi:10.1371/journal.pone.0186937 · Cited by 54 · see citing works
Rapamycin in ischemic stroke: Old drug, new tricks?
Hadley, G., Beard, D. J., Couch, Y., Neuhaus, A., Adriaanse, B. A., DeLuca, G., Sutherland, B. A., & Buchan, A. (2018) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x18807309 · Cited by 53 · see citing works
Role of mTOR inhibitors in epilepsy treatment
Sadowski, K., Kotulska, K., & Jóźwiak, S. (2015) · Pharmacological Reports · doi:10.1016/j.pharep.2014.12.017 · Cited by 51 · see citing works
Impact of aging immune system on neurodegeneration and potential immunotherapies
Liang, Z., Zhao, Y., Ruan, L., Zhu, L., Jin, K., Zhuge, Q., Su, D., & Zhao, Y. L. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.07.006 · Cited by 61 · see citing works
Self-citation
Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures
Yang, M.-T., Lin, Y.-C., Ho, W., Liu, C.-L., & Lee, W.-T. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0797-6 · Cited by 49 · see citing works
“Rapamycin (or sirolimus), the prototype mTOR inhibitor, enhanced the anti-inflammatory activities of regulatory T cells, decreased the production of proinflammatory cytokines and chemokines by macrophages and microglia, and thus attenuated secondary injury after focal ischemia in rats [18].”
Background
Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis
Zimmer, T. S., Broekaart, D. W. M., Gruber, V.-E., van Vliet, E. A., Mühlebner, A., & Aronica, E. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.01028 · Cited by 48 · see citing works
“Treatment with rapamycin or its derivatives everolimus or sirolimus could revert medial cerebral artery occlusion (MCAO)–induced increases of cytokines and/or chemokines, as well as promote anti-inflammatory microglial polarization (222, 223).”
Treg cell: Critical Role of Regulatory T-cells in Depression.
Gao, X., Tang, Y.-R., Kong, L.-L., Fan, Y., Wang, C.-X., & Wang, R. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106893 · Cited by 48 · see citing works
Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proinflammatory diseases, current status, and perspectives
Soltani, A., Bahreyni, A., Boroumand, N., Roshan, M. K., Khazaei, M., Ryzhikov, M., Soleimanpour, S., Avan, A., & Hassanian, S. M. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26276 · Cited by 48 · see citing works
“inhibition of macrophage- and microglia-mediated proinflammatory cytokines and chemokines in ischemic stroke rats (Xie et al., 2014).”
BackgroundInfluential
Inhibition of mammalian target of rapamycin attenuates early brain injury through modulating microglial polarization after experimental subarachnoid hemorrhage in rats.
You, W.-C., Wang, Z., Li, H., Shen, H.-T., Xu, X., Jia, G., & Chen, G. (2016) · Journal of Neurological Sciences · doi:10.1016/j.jns.2016.06.021 · Cited by 48
mTOR pathway: A potential therapeutic target for spinal cord injury
Ding, Y., & Chen, Q. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112430 · Cited by 51 · see citing works
Inhibition of Myeloperoxidase by N-Acetyl Lysyltyrosylcysteine Amide Reduces Oxidative Stress–Mediated Inflammation, Neuronal Damage, and Neural Stem Cell Injury in a Murine Model of Stroke
Yu, G., Liang, Y., Zheng, S., & Zhang, H. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.245688 · Cited by 47 · see citing works
“Several studies found that drugs which downregulate M1 macrophage/microglia and/or upregulate M2 macrophage/microglia polarization are beneficial for MCAO mice to recover from ischemic/reperfusion injury (Jin et al., 2014; Xie et al., 2014).”
Background
Essential Role of mTORC1 in Self-Renewal of Murine Alveolar Macrophages
Deng, W., Yang, J., Lin, X., Shin, J., Gao, J., & Zhong, X. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501845 · Cited by 47 · see citing works
mTOR signaling in immune cells and its implications for cancer immunotherapy.
Zeng, H. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.08.038 · Cited by 44 · see citing works
Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury
Wu, X.-L., Lu, S.-S., Liu, M.-R., Tang, W.-D., Chen, J.-Z., Zheng, Y.-R., Ahsan, A., Cao, M., Jiang, L., Hu, W., et al. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-0361-2 · Cited by 43 · see citing works
“mTOR signaling was reported to regulate neuroinflammation [33, 34], which is involved in the pathological process of cerebral ischemia [35].”
Background
Regulatory T lymphocytes as a therapy for ischemic stroke
Wang, M., Thomson, A., Yu, F., Hazra, R., Junagade, A., & Hu, X.-M. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00975-z · Cited by 40 · see citing works
“Rapamycin Rat Focal ischemic stroke Enhanced anti-inflammatory activity of Tregs; reduced lesion volume; decreased production of pro-inflammatory cytokines by macrophages and microglia [148]”
Background
Protective Role of mTOR in Liver Ischemia/Reperfusion Injury: Involvement of Inflammation and Autophagy
Zhang, T., Guo, J., Gu, J., Chen, K., Li, H.-L., & Wang, J.-L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7861290 · Cited by 40 · see citing works
Self-citation
Autophagy Modulators and Neuroinflammation
Cho, K. S., Lee, J. H., Cho, J., Cha, G., & Song, G. J. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666181031144605 · Cited by 48 · see citing works
Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system
Yamada, D., Kawabe, K., Tosa, I., Tsukamoto, S., Nakazato, R., Kou, M., Fujikawa, K., Nakamura, S., Ono, M., Oohashi, T., et al. (2019) · Communications Biology · doi:10.1038/s42003-019-0582-4 · Cited by 38 · see citing works
Post-Stroke Microglia Induce Sirtuin2 Expression to Suppress the Anti-inflammatory Function of Infiltrating Regulatory T Cells
Shu, L., Xu, C.-Q., Yan, Z.-Y., Yan, Y., Jiang, S.-Z., & Wang, Y.-R. (2019) · Inflammation · doi:10.1007/s10753-019-01057-3 · Cited by 44 · see citing works
“also demonstrate that enhancing the anti-inflammation activity of Tregs can attenuate secondary injury and motor deficits after focal ischemia by to restrain poststroke neuroinflammation [29, 30].”
Background
Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin
Filho, C. D. D. M., Kappeler, L., Dupont, J., Solinc, J., Villapol, S., Denis, C., Nosten‐Bertrand, M., Billard, J., Blaise, A., Tronche, F., et al. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15626718 · Cited by 45 · see citing works
Immunomodulatory effect of CD200-positive human placenta-derived stem cells in the early phase of stroke
Kong, T., Park, J.-M., Jang, J., Kim, C.-Y., Bae, S.-H., Choi, Y., Jeong, Y.-H., Kim, C., Chang, S.-W.-O., Kim, J., et al. (2018) · Experimental and Molecular Medicine · doi:10.1038/emm.2017.233 · Cited by 37 · see citing works
E‐selectin targeted immunoliposomes for rapamycin delivery to activated endothelial cells
Gholizadeh, S., Visweswaran, G. R., Storm, G., Hennink, W., Kamps, J., & Kok, R. (2017) · International journal of pharmaceutics · doi:10.1016/j.ijpharm.2017.10.027 · Cited by 37 · see citing works
“Recent studies have highlighted the pivotal role of the mTOR pathways in inflammatory disorders (Cejka et al., 2010; Xie et al., 2014; Weichhart et al., 2015; Li et al., 2016).”
Background
Inhibition of the Akt1-mTORC1 Axis Alters Venous Remodeling to Improve Arteriovenous Fistula Patency
Guo, X.-J., Fereydooni, A., Isaji, T., Gorecka, J., Liu, S., Hu, H., Ono, S., Alozie, M., Lee, S.-R., Taniguchi, R., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-47542-5 · Cited by 35
RAD001 (everolimus) attenuates experimental autoimmune neuritis by inhibiting the mTOR pathway, elevating Akt activity and polarizing M2 macrophages.
Han, R.-R., Gao, J., Zhai, H., Xiao, J., Ding, Y., & Hao, J. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.04.005 · Cited by 35 · see citing works
The effect of rapamycin treatment on cerebral ischemia: A systematic review and meta-analysis of animal model studies
Beard, D. J., Hadley, G., Thurley, N., Howells, D., Sutherland, B. A., & Buchan, A. (2018) · International Journal of Stroke · doi:10.1177/1747493018816503 · Cited by 34 · see citing works
Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury
Wang, P., He, Y., Li, D., Han, R.-R., Liu, G., Kong, D., & Hao, J. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0660-1 · Cited by 34 · see citing works
“The inhibition of mTORC1 is also believed to prevent the microglial/macrophage phenotype toward to a detrimental state, significantly enhancing beneficial anti-inflammatory activity and decreasing the production of pro-inflammatory cytokines and chemokines [33].”
Background
Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging
Coder, B., Wang, W., Wang, L., Wu, Z., Zhuge, Q., & Su, D. (2016) · Oncotarget · doi:10.18632/oncotarget.12572 · Cited by 35 · see citing works
Self-citation
Sirtuin4 suppresses the anti‐neuroinflammatory activity of infiltrating regulatory T cells in the traumatically injured spinal cord
Lin, W.-P., Chen, W., Liu, W.-F., Xu, Z., & Zhang, L.-Q. (2019) · Immunology · doi:10.1111/imm.13123 · Cited by 32 · see citing works
Hepatic CD206‐positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection
Dai, K.-M., Huang, L., Sun, X.-M., Yang, L.-H., & Gong, Z.-J. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.4a0415-152r · Cited by 32
“[22].”
The role of hypernitrosylation in the pathogenesis and pathophysiology of neuroprogressive diseases
Morris, G., Walder, K. R., Carvalho, A. F., Tye, S. J., Lucas, K., Berk, M., & Maes, M. H. J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.07.017 · Cited by 33 · see citing works
Erythropoietin and Bacillus Calmette–Guérin Vaccination Mitigate 3-Nitropropionic Acid-Induced Huntington-like Disease in Rats by Modulating the PI3K/Akt/mTOR/P70S6K Pathway and Enhancing the Autophagy
Senousy, M. A., Hanafy, M. E., Shehata, N., & Rizk, S. M. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00523 · Cited by 33 · see citing works
Protection by mTOR Inhibition on Zymosan-Induced Systemic Inflammatory Response and Oxidative/Nitrosative Stress: Contribution of mTOR/MEK1/ERK1/2/IKKβ/IκB-α/NF-κB Signalling Pathway
Sahan-Firat, S., Temiz-Resitoglu, M., Guden, D., Kucukkavruk, S. P., Tunçtan, B., Sari, A. N., Kocak, Z., & Malik, K. (2017) · Inflammation · doi:10.1007/s10753-017-0686-2 · Cited by 30 · see citing works
Resveratrol Pretreatment Protected against Cerebral Ischemia/Reperfusion Injury in Rats via Expansion of T Regulatory Cells.
Yang, H.-N., Zhang, A., Zhang, Y., Ma, S., & Wang, C.-L. (2016) · Journal of Stroke & Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2016.04.014 · Cited by 30
Melatonin and Rapamycin Attenuate Isoflurane-Induced Cognitive Impairment Through Inhibition of Neuroinflammation by Suppressing the mTOR Signaling in the Hippocampus of Aged Mice
Yuan, H., Wu, G., Zhai, X., Lu, B., Meng, B., & Chen, J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00314 · Cited by 33 · see citing works
EFFECTS OF RAPAMYCIN ON CEREBRAL OXYGEN SUPPLY AND CONSUMPTION DURING REPERFUSION AFTER CEREBRAL ISCHEMIA
Chi, O., Barsoum, S., Vega-Cotto, N. M., Jacinto, E., Liu, X., Mellender, S., & Weiss, H. R. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.12.045 · Cited by 29 · see citing works
“However, other investigators have suggested that treatment with rapamycin, and therefore inhibition of mTOR, is neuroprotective (Guo et al., 2014; Qi et al., 2014; Xie et al., 2014).”
Background
Involvement of pro-inflammation signal pathway in inhibitory effects of rapamycin on oxaliplatin-induced neuropathic pain
Duan, Z., Su, Z., Wang, H.-S., & Pang, X. (2018) · Molecular Pain · doi:10.1177/1744806918769426 · Cited by 28
“Rapamycin, the prototype of selective mTOR inhibitor, enhances the anti-inflammatory activities of regulatory T cells and decreases the production of PICs and chemokines by macrophages in addition to other immune cells.(23) Recent studies have suggested the role of mTOR in regulating a number of inflammatory and autoi…”
Background
T-cell receptor signaling modulated by the co-receptors: Potential targets for stroke treatment.
Liu, Y., Chen, S., Liu, S., Wallace, K. L., Zille, M., Zhang, J., Wang, J., & Jiang, C. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106797 · Cited by 27 · see citing works
Self-citation
Beneficial Effects of Resveratrol-Mediated Inhibition of the mTOR Pathway in Spinal Cord Injury
Zhou, J., Huo, X., Botchway, B. O. A., Xu, L.-Y., Meng, X., Zhang, S.-O., & Liu, X.-H. (2018) · Journal of Neural Transplantation and Plasticity · doi:10.1155/2018/7513748 · Cited by 27 · see citing works
Emerging Targets for Modulation of Immune Response and Inflammation in Stroke
Thapa, K., Shivam, K., Khan, H., Kaur, A., Dua, K., Singh, S. K., & Singh, T. G. (2023) · Neurochemical Research · doi:10.1007/s11064-023-03875-2 · Cited by 29 · see citing works
“CD28SA, an anti-CD28 antibody, has been shown to boost Treg cell numbers and proliferation [254, 256].”
Background
FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders
Lui, A., Vanleuven, J., Perekopskiy, D., Liu, D., Xu, D., Alzayat, O., Elgokhy, T., Do, T., Gann, M., Martin, R. M., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15121546 · Cited by 35 · see citing works
Effect of hydroxychloroquine on oxidative/nitrosative status and angiogenesis in endothelial cells under high glucose condition
Rezabakhsh, A., Montazersaheb, S., Nabat, E., Hassanpour, M., Montaseri, A., Malekinejad, H., Movassaghpour, A., Rahbarghazi, R., & Garjani, A. (2017) · BioImpacts · doi:10.15171/bi.2017.26 · Cited by 24 · see citing works
Chronic high‐fat diet‐induced obesity in gerbils increases pro‐inflammatory cytokines and mTOR activation, and elicits neuronal death in the striatum following brief transient ischemia
Song, M.-A., Ahn, J., Kim, H., Kim, D. W., Lee, T.-K., Lee, J.-C., Kim, Y.-M., Lee, C.-H., Hwang, I., Yan, B., et al. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.09.009 · Cited by 23 · see citing works
“It has been reported that treatment with rapamycin reduces infarct volume via inhibiting microglia-mediated proinflammatory activity after transient focal cerebral ischemia in rats (Xie et al., 2014).”
mTOR inhibition potentiates cytotoxicity of Vγ4 γδ T cells via up‐regulating NKG2D and TNF‐α
Cao, G.-C., Wang, Q., Li, G., Meng, Z.-Y., Liu, H., Tong, J.-Y., Huang, W., Liu, Z.-H., Jia, Y., Wei, J., et al. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.5a0116-053rr · Cited by 23 · see citing works
Immunohistochemical Assessment of Phosphorylated mTORC1-Pathway Proteins in Human Brain Tumors
Harter, P., Jennewein, L., Baumgarten, P., Ilina, E., Burger, M. C., Thiepold, A., Tichy, J., Zörnig, M., Senft, C., Steinbach, J., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127123 · Cited by 23 · see citing works
“mTOR-activity has been described not only in the context of oncogenic signaling but has also been observed in reactive brain tissue especially in astrocytes and microglia after traumatic brain injuries [31] and stroke [32], while in case of glioma-activated microglia mTOR-inhibition polarized microglia to a M1-phenoty…”
Background
The role of Wnt/mTOR signaling in spinal cord injury
Peng, C. M., Liao, H.-Y., & Zhang, H. (2022) · Journal of Clinical Orthopaedics and Trauma · doi:10.1016/j.jcot.2022.101760 · Cited by 23 · see citing works
The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia
Malone, K., Díaz, A. D., Shearer, J. A., Moore, A., & Waeber, C. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02083-5 · Cited by 24 · see citing works
Diverse functions and mechanisms of regulatory T cell in ischemic stroke.
Wu, Y., Li, J., Shou, J.-Y., Zhang, W.-G., & Chen, C.-H. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113782 · Cited by 21 · see citing works
Adenosine receptors in modulation of central nervous system disorders.
Choudhury, H., Chellappan, D., Sengupta, P., Pandey, M., & Gorain, B. (2019) · Current pharmaceutical design · doi:10.2174/1381612825666190712181955 · Cited by 21 · see citing works
Mammalian Target of Rapamycin at the Crossroad Between Alzheimer’s Disease and Diabetes
Liang, H., Nie, J., Skike, C. E. V., Valentine, J. M., & Orr, M. E. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-3540-2_10 · Cited by 24 · see citing works
Evidence of microglial activation following exposure to serum from first-onset drug-naïve schizophrenia patients
van Rees, G. F., Lago, S. G., Cox, D., Tomasik, J., Rustogi, N., Weigelt, K., Özcan, S., Cooper, J. D., Drexhage, H. A., Leweke, F. M., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.10.003 · Cited by 21 · see citing works
p53 inhibition provides a pivotal protective effect against ischemia-reperfusion injury in vitro via mTOR signaling.
Li, X.-M., Gu, S.-X., Ling, Y., Shen, C., Cao, X.-Y., & Xie, R. (2015) · Brain Research · doi:10.1016/j.brainres.2015.02.009 · Cited by 20 · see citing works
Metformin ameliorates the status epilepticus- induced hippocampal pathology through possible mTOR modulation
Bojja, S., Medhi, B., Anand, S., Bhatia, A., Joshi, R., & Minz, R. (2021) · InflammoPharmacology · doi:10.1007/s10787-020-00782-8 · Cited by 18 · see citing works
Regulatory T cells in ischemic stroke
Wang, H.-Y., Ye, J.-R., Cui, L.-Y., Chu, S.-F., & Chen, N.-H. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00641-4 · Cited by 17 · see citing works
Regulatory T Cells for Stroke Recovery: A Promising Immune Therapeutic Strategy
Li, N., Wang, H.-J., Hu, C., Qie, S.-Y., & Liu, Z.-J. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70248 · Cited by 17 · see citing works
“Combining recombinant IL-2 with the mTOR inhibitor rapamycin and anti-CD3/CD28 beads can achieve selective Treg proliferation by suppressing the proliferation of non-Treg T-cell subsets [98, 99].”
Programmed death protein 1 is essential for maintaining the anti-inflammatory function of infiltrating regulatory T cells in a murine spinal cord injury model
He, X., Lin, S., Lidan, Y., Tan, P., Ma, P., Qiu, P., Zheng, C., Zhang, X., Kang, W., & Lin, W. (2021) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2021.577546 · Cited by 20 · see citing works
P7C3 Suppresses Neuroinflammation and Protects Retinal Ganglion Cells of Rats from Optic Nerve Crush.
Oku, H., Morishita, S., Horie, T., Kida, T., Mimura, M., Kojima, S., & Ikeda, T. (2017) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.17-22179 · Cited by 17 · see citing works
Extension of Microglial Activation is Associated with Epilepsy and Cognitive Dysfunction in Tuberous Sclerosis Complex: A Tspo-Pet Study
Kagitani‐Shimono, K., Kato, H., Soeda, F., Iwatani, Y., Mukai, M., Ogawa, K., Tominaga, K., Nabatame, S., & Taniike, M. (2022) · NeuroImage Clinical · doi:10.1016/j.nicl.2022.103288 · Cited by 17 · see citing works
Rapamycin alleviates proinflammatory cytokines and nociceptive behavior induced by chemotherapeutic paclitaxel
Zhang, X.-L., Jiang, N., Li, J., Zhang, D.-Y., & Lv, X. (2018) · Neurological Research · doi:10.1080/01616412.2018.1531199 · Cited by 16
“selective mTOR inhibitor, enhances the anti-inflammatory activities of regulatory T cells and decreases the production of PICs and chemokines by macrophages in addition to other immune cells [24].”
Background
The CD40/CD40L system regulates rat cerebral microvasculature after focal ischemia/reperfusion via the mTOR/S6K signaling pathway
Jiang, R.-H., Xu, X.-Q., Wu, C.-J., Lu, S.-S., Zu, Q., Zhao, L.-B., Liu, S., & Shi, H.-B. (2018) · Neurological Research · doi:10.1080/01616412.2018.1473075 · Cited by 16
“pathway plays an important part in ischemic stroke, and the inhibition of mTORC1 signaling may be a protective mechanism [14].”
Background

Authors: Xie, L., Sun, F., Wang, J., Mao, X., Xie, L., Yang, S.-H., Su, D.-M., Simpkins, J. W., Greenberg, D. A., & Jin, K.
Affiliations: Buck Institute for Research on Aging (US)
University of North Texas Health Science Center (US)
West Virginia University (US)
Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer’s Disease Research, University of North Texas Health Science Center , Fort Worth, TX 76107
Corresponding author: Xie, Luokun
Sun, Fen
Wang, Jixian
ORCID: Sun, Fen
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2014-06
Volume: 192
Issue: 12
Pages: 6009-6019
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.1303492
PMC: PMC4128178
OpenAlex: W1618035875
Cited by: 175
References: 76
Citations by year: 2026: 4 · 2025: 9 · 2024: 6 · 2023: 19 · 2022: 11 · 2021: 26 · 2020: 12 · 2019: 19 · 2018: 15 · 2017: 18 · 2016: 21 · 2015: 12 · 2014: 2 · 2012: 1
FWCI: 9.20
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
The Research Repository @ WVU (West Virginia University) (submittedVersion)
Funders: University of North Texas
National Institute on Aging (R01AG021980, AG21980, P01AG027956)
National Institute of General Medical Sciences (U54GM104942)
National Institute of Neurological Disorders and Stroke (NS57186, NS054651, NS054687, R01NS054687, R01NS057186, R01NS054651)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords: mTOR signaling, rapamycin, focal ischemic stroke, regulatory T cells, macrophage polarization, microglia, γδ T cells, granulocytes, inflammatory cytokines, chemokines, secondary brain injury, motor impairment, intracerebroventricular administration
MeSH terms: Animals, Brain Ischemia, Immunosuppressive Agents, Inflammation, Macrophages, Male, Signal Transduction, Receptors, Antigen, T-Cell, gamma-delta, Rats, Sprague-Dawley, Microglia, Sirolimus, Stroke, T-Lymphocytes, Regulatory, Rats, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Record

About these checks