TGFβ signalling plays an important role in IL4-induced alternative activation of microglia
Open accessAbstract
BACKGROUND: Microglia are the resident immune cells of the central nervous system and are accepted to be involved in a variety of neurodegenerative diseases. Several studies have demonstrated that microglia, like peripheral macrophages, exhibit two entirely different functional activation states, referred to as classical (M1) and alternative (M2) activation. TGFβ is one of the most important anti-inflammatory cytokines and its effect on inhibiting microglia or macrophage classical activation has been extensively studied. However, the role of TGFβ during alternative activation of microglia has not been described yet. METHODS: To investigate the role of TGFβ in IL4-induced microglia alternative activation, both, BV2 as well as primary microglia from new born C57BL/6 mice were used. Quantitative RT-PCR and western blots were performed to detect mRNA and protein levels of the alternative activation markers Arginase1 (Arg1) and Chitinase 3-like 3 (Ym1) after treatment with IL4, TGFβ or both. Endogenous TGFβ release after IL4 treatment was evaluated using the mink lung epithelial cell (MLEC) assay and a direct TGFβ2 ELISA. TGFβ receptor type I inhibitor and MAPK inhibitor were applied to address the involvement of TGFβ signalling and MAPK signalling in IL4-induced alternative activation of microglia. RESULTS: TGFβ enhances IL4-induced microglia alternative activation by strongly increasing the expression of Arg1 and Ym1. This synergistic effect on Arg1 induction is almost completely blocked by the application of the MAPK inhibitor, PD98059. Further, treatment of primary microglia with IL4 increased the expression and secretion of TGFβ2, suggesting an involvement of endogenous TGFβ in IL4-mediated microglia activation process. Moreover, IL4-mediated induction of Arg1 and Ym1 is impaired after blocking the TGFβ receptor I indicating that IL4-induced microglia alternative activation is dependent on active TGFβ signalling. Interestingly, treatment of primary microglia with TGFβ alone results in up regulation of the IL4 receptor alpha, indicating that TGFβ increases the sensitivity of microglia for IL4 signals. CONCLUSIONS: Taken together, our data reveal a new role for TGFβ during IL4-induced alternative activation of microglia and consolidate the essential functions of TGFβ as an anti-inflammatory molecule and immunoregulatory factor for microglia.
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
Cites
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?
In AD brains, activated microglia and astrocytes are present around Aβ plaques, with release of inflammatory cytokines such as IL-1, IL-6, TNF-α and transforming growth factor-β.
“it was observed in AD brains the presence of activated microglia and astrocytes around Aβ plaques, with the release of inflammatory cytokines, such as IL-1 and IL-6, TNF-α and transforming growth factor-β (TNF-β; Wyss-Coray, 2006; Zhou et al., 2012).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Zhou et al., 2012
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144 · see citing works
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · see citing works
Monocyte and macrophage heterogeneity
Gordon, S., & Taylor, P. R. (2005) · Nature Reviews Immunology · doi:10.1038/nri1733 · Cited by 5,190 · see citing works
Obesity induces a phenotypic switch in adipose tissue macrophage polarization
Lumeng, C. N., Bodzin, J. L., & Saltiel, A. R. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29881 · Cited by 4,664 · see citing works
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110 · see citing works
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · cited 2× · see citing works
“Whereas TGFβ induces acquired deactivation, the acquired deactivation macrophages also produce TGFβ in an autocrine manner [3,24,25].”
BackgroundAlternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745 · see citing works
Role of Transforming Growth Factor β in Human Disease
Blobe, G. C., Schiemann, W. P., & Lodish, H. F. (2000) · New England Journal of Medicine · doi:10.1056/nejm200005043421807 · Cited by 2,430 · see citing works
TRANSFORMING GROWTH FACTOR-β REGULATION OF IMMUNE RESPONSES
Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A.-K. L., & Flavell, R. A. (2005) · Annual Review of Immunology · doi:10.1146/annurev.immunol.24.021605.090737 · Cited by 2,199 · see citing works
The many faces of macrophage activation
Mosser, D. M. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0602325 · Cited by 1,902 · see citing works
SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS
Feng, X.-H., & Derynck, R. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.022404.142018 · Cited by 1,869 · see citing works
Fibrotic disease and the TH1/TH2 paradigm
Wynn, T. A. (2004) · Nature Reviews Immunology · doi:10.1038/nri1412 · Cited by 1,765 · see citing works
Macrophage deactivation by interleukin 10.
Bogdan, C., Yoram Vodovotz, B., & Nathan, C. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.174.6.1549 · Cited by 1,236 · see citing works
Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain
Colton, C. A. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9164-4 · Cited by 871 · see citing works
Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression
Gao, H., & Hong, J. (2008) · Trends in Immunology · doi:10.1016/j.it.2008.05.002 · Cited by 822 · see citing works
Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M., & Weiner, H. L. (2011) · Nature Medicine · doi:10.1038/nm.2266 · Cited by 787 · see citing works
Abe, M., Harpel, J. G., Metz, C. N., Nunes, I., Loskutoff, D. J., & Rifkin, D. B. (1994) · Analytical Biochemistry · doi:10.1006/abio.1994.1042 · Cited by 757 · see citing works
Massagué, J., & Gomis, R. R. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.04.033 · Cited by 719 · see citing works
Hesse, M., Modolell, M., Flamme, A. C. L., Schito, M. L., Fuentes, J. M., Cheever, A. W., Pearce, E. J., & Wynn, T. A. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.11.6533 · Cited by 706 · see citing works
Munder, M., Eichmann, K., & Modolell, M. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.11.5347 · Cited by 647 · see citing works
Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox
Rubartelli, A., & Lotze, M. T. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.08.004 · Cited by 614 · see citing works
Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-10
Lang, R., Patel, D. H., Morris, J. J., Rutschman, R. L., & Murray, P. J. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.5.2253 · Cited by 613 · see citing works
Interdependent SMAD and JNK Signaling in Transforming Growth Factor-β-mediated Transcription
Engel, M. E., McDonnell, M. A., Law, B. K., & Moses, H. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.37413 · Cited by 531 · see citing works
Ameboid microglia as effectors of inflammation in the central nervous system
Giulian, D. (1987) · Journal of Neuroscience Research · doi:10.1002/jnr.490180123 · Cited by 482 · see citing works
The microglial "activation" continuum: from innate to adaptive responses
Town, T., Nikolic, V., & Tan, J. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-24 · Cited by 456 · see citing works
Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology
Town, T., Laouar, Y., Pittenger, C., Mori, T., Szekely, C. A., Tan, J., Duman, R. S., & Flavell, R. A. (2008) · Nature Medicine · doi:10.1038/nm1781 · Cited by 422 · see citing works
Assessing Activation States in Microglia
Colton, C. A., & Wilcock, D. M. (2010) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152710791012053 · Cited by 421 · see citing works
Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease
Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., & Mucke, L. (1997) · Nature · doi:10.1038/39321 · Cited by 417 · see citing works
Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD.
(2006) · Journal of Neuroinflammation · doi:10.1186/1742-2094-3-27 · Cited by 393 · see citing works
Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease
Rojo, A. I., Innamorato, N. G., Martín-Moreno, A. M., CEBALLOS, M. L. D., Yamamoto, M. P., & Cuadrado, A. (2009) · Glia · doi:10.1002/glia.20947 · Cited by 381 · see citing works
Enzymes of Arginine Metabolism
Morris, S. M. (2004) · Journal of Nutrition · doi:10.1093/jn/134.10.2743s · Cited by 357 · see citing works
Ponomarev, E. D., Maresz, K., Tan, Y., & Dittel, B. N. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1922-07.2007 · Cited by 339 · see citing works
Transforming growth factor-beta suppresses activation and proliferation of microglia in vitro.
Suzumura, A., Sawada, M., Yamamoto, H., & Marunouchi, T. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.4.2150 · Cited by 305 · see citing works
Vaughan, D. W., & Peters, A. (1974) · Journal of Neurocytology · doi:10.1007/bf01098730 · Cited by 301 · see citing works
The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically?
Gregory, C. D., & Devitt, A. (2004) · Immunology · doi:10.1111/j.1365-2567.2004.01959.x · Cited by 285 · see citing works
A Macrophage Protein, Ym1, Transiently Expressed during Inflammation Is a Novel Mammalian Lectin*
Chang, N., Hung, S.-I., Hwa, K., Kato, I., Chen, J.-E., Liu, C.-H., & Chang, A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010417200 · Cited by 276 · see citing works
Loke, P., Gallagher, I., Nair, M. G., Zang, X., Brombacher, F., Mohrs, M., Allison, J. P., & Allen, J. E. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3926 · Cited by 274 · see citing works
Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma
Oh, C. K., Geba, G. P., & Molfino, N. A. (2010) · European Respiratory Review · doi:10.1183/09059180.00007609 · Cited by 257 · see citing works
Enhancer-Mediated Control of Macrophage-Specific Arginase I Expression
Pauleau, A., Rutschman, R. L., Lang, R., Pernis, A. B., Watowich, S. S., & Murray, P. J. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.12.7565 · Cited by 243 · see citing works
Gotoh, T., Sonoki, T., Nagasaki, A., Terada, K., Takiguchi, M., & Mori, M. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)01015-0 · Cited by 236 · see citing works
Differential regulation of macrophage arginine metabolism: a proposed role in wound healing
Shearer, J. D., Richards, J. R., Mills, C. D., & Caldwell, M. D. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.2.e181 · Cited by 229 · see citing works
Boutard, V., Havouis, R., Fouqueray, B. L., Philippe, C., Moulinoux, J.-P., & Baud, L. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.4.2077 · Cited by 186 · see citing works
IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia
Shimizu, E., Kawahara, K., Kajizono, M., Sawada, M., & Nakayama, H. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.9.6503 · Cited by 143 · see citing works
Griffiths, M., Gasque, P., & Neal, J. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181996688 · Cited by 130 · see citing works
Loane, D. J., Stoica, B. A., Pajoohesh‐Ganji, A., Byrnes, K. R., & Faden, A. I. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806139200 · Cited by 119 · see citing works
IL-10 expression profiling in human monocytes
Williams, L. M., Járai, G., Smith, A. J., & Finan, P. M. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.4.800 · Cited by 113 · see citing works
Transforming Growth Factor-β: A Neuroprotective Factor in Cerebral Ischemia
Dhandapani, K. M., & Brann, D. W. (2003) · Cell Biochemistry and Biophysics · doi:10.1385/cbb:39:1:13 · Cited by 111 · see citing works
Functional role and species-specific contribution of arginases in pulmonary fibrosis
Kitowska, K., Zakrzewicz, D., Königshoff, M., Chrobak, I., Grimminger, F., Seeger, W., Bulau, P., & Eickelberg, O. (2007) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00007.2007 · Cited by 98 · see citing works
Basu, A., Krady, J. K., Enterline, J. R., & Levison, S. W. (2002) · Glia · doi:10.1002/glia.10118 · Cited by 83 · see citing works
Ma, T. C., Campana, A., Lange, P. S., Lee, H., Banerjee, K., Bryson, J. B., Mahishi, L., Alam, S., Giger, R. J., Barnes, S., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5266-09.2010 · Cited by 79 · see citing works
Herrera‐Molina, R., & Rommy von Bernhardi, M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.01.003 · Cited by 74 · see citing works
Upregulation of Arginase Expression in Wound-Derived Fibroblasts
Witte, M. B., Barbul, A., Schick, M. A., Vogt, N., & Becker, H. D. (2002) · Journal of Surgical Research · doi:10.1006/jsre.2002.6443 · Cited by 72 · see citing works
Nio‐Kobayashi, J., Fujimoto, W., Konno, A., Kon, Y., Owhashi, M., & Iwanaga, T. (2004) · Histochemistry and Cell Biology · doi:10.1007/s00418-004-0654-4 · Cited by 66 · see citing works
TGF-β1 Disrupts Endotoxin Signaling in Microglial Cells through Smad3 and MAPK Pathways
Le, Y., Iribarren, P., Gong, W., Cui, Y., Zhang, X., & Wang, J. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.2.962 · Cited by 58 · see citing works
Kitamura, Y., Takahashi, H., Matsuoka, Y., Tooyama, I., Kimura, H., Nomura, Y., & Taniguchi, T. (1996) · Glia · doi:10.1002/(sici)1098-1136(199611)18:3 · Cited by 46 · see citing works
Alternative Aβ Immunotherapy Approaches for Alzheimers Disease
Town, T. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787847306 · Cited by 42 · see citing works
Inflammation in Parkinson's disease: an update.
Smith, P. F. (2008) · PubMed · Cited by 41 · see citing works
Accumulation of Ym1/2 protein in the mouse olfactory epithelium during regeneration and aging
Giannetti, N., Moyse, E., Ducray, A., Bondier, J., Jourdan, F., Propper, A. Y., & Kästner, A. (2003) · Neuroscience · doi:10.1016/j.neuroscience.2003.09.024 · Cited by 37 · see citing works
Determination of Mammalian Arginase Activity
Kepka‐Lenhart, D., Ash, D. E., & Morris, S. M. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(07)00813-0 · Cited by 32 · see citing works
TGF-β2reduces nitric oxide synthase mRNA through a ROCK-dependent pathway in airway epithelial cells
Jiang, J., & George, S. C. (2011) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00464.2010 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Tang, Y., & Le, W. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9070-5 · Cited by 2,190 · see citing works
Peripheral inflammation and blood–brain barrier disruption: effects and mechanisms
Huang, X., Hussain, B., & Chang, J. (2020) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13569 · Cited by 732 · see citing works
The biphasic function of microglia in ischemic stroke
Ma, Y., Wang, J., Wang, Y., & Yang, G. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.01.005 · Cited by 724 · see citing works
Alternatively activated microglia and macrophages in the central nervous system
Franco, R., & Fernández‐Suárez, D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.003 · Cited by 650 · see citing works
The impact of microglial activation on blood-brain barrier in brain diseases
da Fonseca, A. C. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., & Lima, F. R. S. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00362 · Cited by 572 · see citing works
Microglia and ischemic stroke: a double-edged sword.
Patel, A. R., Ritzel, R. M., McCullough, L. D., & Liu, F. (2013) · Europe PMC (PubMed Central) · Cited by 355 · see citing works
Wattananit, S., Tornero, D., Graubardt, N., Memanishvili, T., Monni, E., Tatarishvili, J., Miskinyte, G., Ge, R., Ahlenius, H., Lindvall, O., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4317-15.2016 · Cited by 354 · see citing works
Microglial Dysregulation in Psychiatric Disease
Frick, L. R., Williams, K., & Pittenger, C. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/608654 · Cited by 299 · see citing works
Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases
Spittau, B. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00194 · Cited by 258 · see citing works
Self-citationHussain, B., Fang, C., & Chang, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.688090 · Cited by 251 · see citing works
Treatment targets for M2 microglia polarization in ischemic stroke
Wang, J., Xing, H., Wan, L., Jiang, X., wang, C., & Wu, Y. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.05.143 · Cited by 229 · see citing works
Yanguas‐Casás, N., Barreda‐Manso, M. A., Nieto‐Sampedro, M., & Romero‐Ramírez, L. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25742 · Cited by 223 · see citing works
Lively, S. S., & Schlichter, L. C. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-75 · Cited by 208 · see citing works
Targeting the Microglial Signaling Pathways: New Insights in the Modulation of Neuropathic Pain
Popiołek-Barczyk, K., & Mika, J. (2016) · Current Medicinal Chemistry · doi:10.2174/0929867323666160607120124 · Cited by 203 · see citing works
Parodi, B., Rossi, S., Morando, S., Cordano, C., Bragoni, A., Motta, C., Usai, C., Wipke, B. T., Scannevin, R. H., Mancardi, G., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1422-3 · Cited by 196 · see citing works
Functional diversity of microglia – how heterogeneous are they to begin with?
Hanisch, U.-K. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00065 · Cited by 195 · see citing works
Microglial Phenotype and Adaptation
Eggen, B. J. L., Raj, D. D. A., Hanisch, U., & Boddeke, H. W. G. M. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9490-4 · Cited by 176 · see citing works
Cai, Q., Li, Y., & Pei, G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0839-0 · Cited by 154 · see citing works
Neuroimmune mechanisms and therapies mediating post-ischaemic brain injury and repair
Shichita, T., Ooboshi, H., & Yoshimura, A. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00690-0 · Cited by 145 · see citing works
Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke
Lee, Y., Lee, S., Choi, S. S., Yeo, H.-G., Chang, K., & Lee, H. J. (2014) · BioMed Research International · doi:10.1155/2014/297241 · Cited by 143 · see citing works
Xiao, M., Liu, C. X., Zhou, L. G., Yang, Y., & Wang, Y. (2023) · Medicine · doi:10.1097/md.0000000000032991 · Cited by 138 · see citing works
Blood-brain barrier integrity in the pathogenesis of Alzheimer’s disease
Huang, Z., Wong, L., Su, Y., Huang, X., Wang, N., Chen, H., & Yi, C. (2020) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2020.100857 · Cited by 130 · see citing works
Interferon regulatory factor 7 participates in the M 1‐like microglial polarization switch
Tanaka, T., Murakami, K., Bandô, Y., & Yoshida, S. (2014) · Glia · doi:10.1002/glia.22770 · Cited by 122 · see citing works
Protective Microglia and Their Regulation in Parkinson’s Disease
Le, W., Wu, J., & Tang, Y. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00089 · Cited by 112 · see citing works
Natural Products as a Potential Modulator of Microglial Polarization in Neurodegenerative Diseases
Jin, X., Liu, M.-Y., Zhang, D.-F., Zhong, X., Du, K., Qian, P., Gao, H., & Wei, M.-J. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104253 · Cited by 109 · see citing works
Li, X., Shi, H., Zhang, D., Jing, B., Chen, Z., Zheng, Y., Chang, S., Gao, L., & Zhao, G. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14211 · Cited by 96 · see citing works
A novel cell line from spontaneously immortalized murine microglia
Nagamoto‐Combs, K., Kulas, J. A., & Combs, C. K. (2014) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2014.05.021 · Cited by 95 · see citing works
Activation of Nrf2 Pathway Contributes to Neuroprotection by the Dietary Flavonoid Tiliroside
Velagapudi, R., El-Bakoush, A., & Olajide, O. A. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0975-2 · Cited by 91 · see citing works
Targeting IL-13 and IL-4 in Asthma: Therapeutic Implications on Airway Remodeling in Severe Asthma
Sahnoon, L., Bajbouj, K., Mahboub, B., Hamoudi, R., & Hamid, Q. A. (2025) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-025-09045-2 · Cited by 89 · see citing works
Ganbold, T., Bao, Q., Zandan, J., Hasi, A., & Baigude, H. (2020) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.9b23004 · Cited by 79 · see citing works
Involvement of MicroRNA in Microglia-Mediated Immune Response
Guedes, J. R., Cardoso, A. L., & de Lima, M. C. P. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/186872 · Cited by 79 · see citing works
Shen, Z., Bao, X., & Wang, R. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00314 · Cited by 77 · see citing works
TGF-β1 Neuroprotection via Inhibition of Microglial Activation in a Rat Model of Parkinson’s Disease
Chen, X., Liu, Z., Cao, B., Qiu, Y., & Peng, Y.-P. (2017) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-017-9732-y · Cited by 77 · see citing works
Resolvin D1 promotes the interleukin-4-induced alternative activation in BV-2 microglial cells
Li, L., Wu, Y., Wang, Y., Wu, J., Song, L., Xian, W., Yuan, S., Pei, L., & Shang, Y. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-72 · Cited by 77 · see citing works
Role of Microglial Activation in the Pathophysiology of Bacterial Meningitis
Barichello, T., Generoso, J. S., Simões, L. R., Goularte, J. A., Petronilho, F. C., Saigal, P., Badawy, M., & Quevedo, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9107-4 · Cited by 76 · see citing works
Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination
Jackson, C. M., Kochel, C. M., Nirschl, C. J., Durham, N. M., Ruzevick, J., Alme, A., Francica, B. J., Elias, J., Daniels, A., Dubensky, T. W., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1516 · Cited by 74 · see citing works
Kumar, A., Bhatia, H. S., de Oliveira, A. C. P., & Fiebich, B. L. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13364 · Cited by 69 · see citing works
Mao, R., Zhang, C., Chen, J., Zhao, G., Zhou, R., Wang, F., Xu, J., Yang, T., Su, Y., Huang, J., et al. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.04.115 · Cited by 68 · see citing works
MacDowell, K. S., Munarriz‐Cuezva, E., Caso, J. R., Madrigal, J. L. M., Zabala, A., Meana, J. J., García‐Bueno, B., & Leza, J. C. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.12.025 · Cited by 67 · see citing works
Quarta, A., Berneman, Z. N., & Ponsaerts, P. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.03.023 · Cited by 67 · see citing works
McCarthy, R. C., Lu, D., Alkhateeb, A. A., Gardeck, A. M., Lee, C., & Wessling‐Resnick, M. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0484-z · Cited by 67 · see citing works
Ferreira, R., Lively, S. S., & Schlichter, L. C. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00183 · Cited by 65 · see citing works
Actin dynamics shape microglia effector functions.
Uhlemann, R., Gertz, K., Boehmerle, W., Schwarz, T., Nolte, C., Freyer, D., Kettenmann, H., Endres, M., & Kronenberg, G. (2016) · Brain Structure and Function · doi:10.1007/s00429-015-1067-y · Cited by 61 · see citing works
The Role of Glial Cells in Synaptic Dysfunction: Insights into Alzheimer's Disease Mechanisms
Yu, Y., Chen, R., Mao, K., Deng, M., & Li, Z. (2023) · Aging and Disease · doi:10.14336/ad.2023.0718 · Cited by 60 · see citing works
He, L., Zheng, Y., Huang, L., Ye, J., Ye, Y., Luo, H., Chen, X., Yao, W., Chen, J., & Zhang, J. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02227-y · Cited by 57 · see citing works
Cengiz, P., Zafer, D., Chandrashekhar, J. H., Chanana, V., Bogost, J., Waldman, A. D., Novak, B., Kintner, D. B., & Ferrazzano, P. A. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2018.12.016 · Cited by 57 · see citing works
Tuftsin signals through its receptor neuropilin‐1 via the transforming growth factor beta pathway
Nissen, J. C., Selwood, D. L., & Tsirka, S. E. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12404 · Cited by 56 · see citing works
Yuan, Y., Fang, M., Wu, C., & Ling, E. (2016) · NeuroMolecular Medicine · doi:10.1007/s12017-016-8394-x · Cited by 55 · see citing works
Importance of GPCR-Mediated Microglial Activation in Alzheimer’s Disease
Haque, M. E., Kim, I., Jakaria, M., Akther, M., & Choi, D. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00258 · Cited by 55 · see citing works
Dynamic response of microglia/macrophage polarization following demyelination in mice
Chu, T., Zhang, Y. P., Tian, Z., Ye, C., Zhu, M., Shields, L. B. E., Kong, M., Barnes, G. N., Shields, C. B., & Cai, J. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1586-1 · Cited by 54 · see citing works
Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force?
Isaković, J., Šerer, K., Barišić, B., & Mitrečić, D. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1139359 · Cited by 53 · see citing works
Thorsdottir, S., Henriques‐Normark, B., & Iovino, F. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.00576 · Cited by 52 · see citing works
Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
Chatterjee, J., Sanapala, S., Cobb, O. M., Bewley, A. F., Goldstein, A. K., Cordell, E., Ge, X., Garbow, J. R., Holtzman, M. J., & Gutmann, D. H. (2021) · Nature Communications · doi:10.1038/s41467-021-27455-6 · Cited by 50 · see citing works
Zhou, X., Zöller, T., KRIEGLSTEIN, K. G., & Spittau, B. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13111 · Cited by 50 · see citing works
Self-citationAttaai, A., Neidert, N. N., von Ehr, A., Potru, P. S., Zöller, T., & Spittau, B. (2018) · Glia · doi:10.1002/glia.23332 · Cited by 48 · see citing works
Self-citationAn update on Ym1 and its immunoregulatory role in diseases
Kang, Q., Li, L., Pang, Y., Zhu, W., & Meng, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.891220 · Cited by 46 · see citing works
He, C., Jiang, J., Liu, J., Zhou, L., Ge, Y., & Yang, Z. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.132372 · Cited by 44 · see citing works
Haas, S. J.-P., Zhou, X., Machado, V., Wree, A., KRIEGLSTEIN, K. G., & Spittau, B. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00007 · Cited by 44 · see citing works
Self-citationHe, H.-J., Cao, L., Wang, Z., Wang, Z., Miao, J., Li, X.-M., & Miao, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.736479 · Cited by 44 · see citing works
Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke
Dugue, R., Nath, M., Dugue, A. G., & Barone, F. C. (2017) · InTech eBooks · doi:10.5772/intechopen.70099 · Cited by 43 · see citing works
Tang, R., Cao, Q., Hu, S.-W., He, L., Du, P., Chen, G., Fu, R., Xiao, F., Sun, Y., Zhang, J., et al. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00727-z · Cited by 42 · see citing works
Neuroinflammation in Alzheimer’s Disease: Microglia, Molecular Participants and Therapeutic Choices
Wang, H., Shen, Y., Chuang, H.-Y., Chiu, C., Ye, Y., & Zhao, L. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190503151648 · Cited by 42 · see citing works
So, Y.-J., Lee, J.-U., Yang, G.-S., Yang, G., Kim, S. W., Lee, J., & Kim, J.-U. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021071 · Cited by 41 · see citing works
Mitchell, K., Shah, J. P., Tsytsikova, L. V., Campbell, A., Affram, K. O., & Symes, A. J. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12612 · Cited by 41 · see citing works
Izquierdo‐Altarejos, P., Cabrera‐Pastor, A., Martinez‐García, M., Sánchez-Huertas, C., Hernández, A., Moreno‐Manzano, V., & Felipo, V. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02688-4 · Cited by 40 · see citing works
Neidert, N. N., von Ehr, A., Zöller, T., & Spittau, B. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01728 · Cited by 39 · see citing works
Self-citationGuo, D., Yamamoto, M., Hernandez, C. M., Khodadadi, H., Baban, B., & Stranahan, A. M. (2021) · Nature Communications · doi:10.1038/s41467-021-24540-8 · Cited by 38 · see citing works
Radpour, M., Khoshkroodian, B., Asgari, T., Pourbadie, H. G., & Sayyah, M. (2023) · Inflammation · doi:10.1007/s10753-023-01843-0 · Cited by 37 · see citing works
Szymura, J., Kubica, J., Więcek, M., & Pera, J. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9010184 · Cited by 37 · see citing works
Yanguas‐Casás, N., Barreda-Manso, M. A., Pérez-Rial, S., Nieto‐Sampedro, M., & Romero‐Ramírez, L. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0142-6 · Cited by 36 · see citing works
Goudarzi, S., Gilchrist, S. E., & Hafizi, S. (2020) · Cells · doi:10.3390/cells9081779 · Cited by 35 · see citing works
Iwahara, N., Hisahara, S., Kawamata, J., Matsumura, A., Yokokawa, K., Saito, T., Fujikura, M., Manabe, T., Suzuki, H., Matsushita, T., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160887 · Cited by 34 · see citing works
Zhang, Z., Zhang, X., Wang, C., Teng, W., Xing, H., Wang, F., Yinwang, E., Sun, H., Wu, Y., Yu, C., et al. (2022) · Chemical Engineering Journal · doi:10.1016/j.cej.2021.134465 · Cited by 33 · see citing works
de Almeida, E. J. R., Ibrahim, H. J., Schetinger, M. R. C., de Andrade, C. M., & Cardoso, A. M. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03713-x · Cited by 33 · see citing works
Growth/differentiation factor-15 and its role in peripheral nervous system lesion and regeneration
Wang, X., Krebbers, J., Charalambous, P., Machado, V., Schober, A., Bosse, F., Müller, H.-W., & Unsicker, K. (2015) · Cell and Tissue Research · doi:10.1007/s00441-015-2219-3 · Cited by 33 · see citing works
Mohammad, Z. B., Yudin, S. C. Y., Goldberg, B. J., Serra, K. L., & Klegeris, A. (2024) · Reviews in the Neurosciences · doi:10.1515/revneuro-2024-0081 · Cited by 32 · see citing works
Zhao, N., Hao, X.-N., Huang, J.-M., Song, Z., & Tao, Y. (2024) · Aging and Disease · doi:10.14336/ad.2023.0823-3 · Cited by 32 · see citing works
The promise of the TGF-β superfamily as a therapeutic target for Parkinson's disease
Karampetsou, M., Vekrellis, K., & Melachroinou, K. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105805 · Cited by 31 · see citing works
Izquierdo‐Altarejos, P., Moreno‐Manzano, V., & Felipo, V. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.375301 · Cited by 31 · see citing works
Functional Roles of the Ca2+-activated K+ Channel, KCa3.1, in Brain Tumors
D’Alessandro, G., Limatola, C., & Catalano, M. (2018) · Current Neuropharmacology · doi:10.2174/0929867324666170713103621 · Cited by 30 · see citing works
The Arginase Pathway in Neonatal Brain Hypoxia-Ischemia
Mike, J. K., Pathipati, P., Russ, J. B., Sheldon, A., & Ferriero, D. M. (2018) · Developmental Neuroscience · doi:10.1159/000496467 · Cited by 29 · see citing works
Spittau, B., Rilka, J., Steinfath, E., Zöller, T., & KRIEGLSTEIN, K. G. (2014) · Glia · doi:10.1002/glia.22740 · Cited by 28 · see citing works
Self-citationYousefi, N., Sotoodehnejadnematalahi, F., Heshmati-Fakhr, N., Sayyah, M., Hoseini, M., Ghassemi, S., Aliakbari, S., & Pourbadie, H. G. (2019) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1249-1 · Cited by 28 · see citing works
Inhibition of Microglial TGFβ Signaling Increases Expression of Mrc1
von Ehr, A., Attaai, A., Neidert, N. N., Potru, P. S., Ruß, T., Zöller, T., & Spittau, B. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00066 · Cited by 28 · see citing works
Self-citationInduction of Transforming Growth Factor Beta Receptors following Focal Ischemia in the Rat Brain
Pál, G., Lovas, G., & Dobolyi, Á. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106544 · Cited by 27 · see citing works
Lively, S. S., Lam, D., Wong, R., & Schlichter, L. C. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00115 · Cited by 27 · see citing works
Microglia in retinal diseases: From pathogenesis towards therapeutic strategies
Xiao, R., Huang, X., Gao, S., Duan, J., Zhang, Y., & Zhang, M. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116550 · Cited by 26 · see citing works
Hühner, L., Rilka, J., Gilsbach, R., Zhou, X., Machado, V., & Spittau, B. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00062 · Cited by 25 · see citing works
Self-citationBarbalace, M. C., Freschi, M., Rinaldi, I., Mazzara, E., Maraldi, T., Malaguti, M., Prata, C., Maggi, F., Petrelli, R., Hrelia, S., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316601 · Cited by 24 · see citing works
Differential response to intrahippocampal interleukin-4/interleukin-13 in aged and exercise mice
Littlefield, A. M., & Kohman, R. A. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.11.027 · Cited by 24 · see citing works
Ahuja, S., & Lazar, I. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.646043 · Cited by 23 · see citing works
Spittau, B. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.215250 · Cited by 23 · see citing works
Self-citationYu, T., Yu, H., Zhang, B., Wang, D., Li, B., Zhu, J., & Zhu, W. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.03.002 · Cited by 22 · see citing works
Exploring the role of microglia in mood disorders associated with experimental multiple sclerosis
Gentile, A., Vito, F. D., Fresegna, D., Musella, A., Buttari, F., Bullitta, S., Mandolesi, G., & Centonze, D. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00243 · Cited by 22 · see citing works
Lawrimore, C. J., Coleman, L. G., Zou, J., & Crews, F. T. (2019) · Brain Sciences · doi:10.3390/brainsci9090228 · Cited by 21 · see citing works
Ding, Y., Zhou, M., Zheng, R., Ma, R., Deng, J., Hao, W., Wang, L., Zhang, J.-C., Ho, C.-T., & Huang, J. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154512 · Cited by 21 · see citing works
Lee, J. H., Lee, B. H., Jeong, S., Joh, C. S.-Y., Nam, H. J., Choi, H. S., Sserwadda, H., Oh, J. W., Park, C., Jin, S., et al. (2023) · Genomics & Informatics · doi:10.5808/gi.23009 · Cited by 21 · see citing works
Zhu, H., Liu, J., Zhou, J., Jin, Y., Zhao, Q., Jiang, X., & Gao, H. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118651 · Cited by 21 · see citing works
Okutani, H., Yamanaka, H., Kobayashi, K., Okubo, M., & Noguchi, K. (2018) · Glia · doi:10.1002/glia.23340 · Cited by 20 · see citing works
Zhang, Q., Liu, Z., Li, B., Mu, L., Sheng, K., Xiong, Y., Cheng, J., Zhou, J., Xiong, Z. L., Zhou, L., et al. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202303027 · Cited by 20 · see citing works
- Authors
- Zhou, X., Spittau, B., & Krieglstein, K.
- Affiliations
- University of Freiburg (DE)
- Corresponding author
- Spittau, Björn
- Krieglstein, Kerstin
- Venue
- Journal of Neuroinflammation
- Published
- 2012-09-04
- Volume
- 9
- Issue
- 1
- Pages
- 210-210
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC3488564
- OpenAlex
- W2128215483
- Cited by
- 159
- References
- 60
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 16 · 2023: 13 · 2022: 11 · 2021: 14 · 2020: 10 · 2019: 10 · 2018: 13 · 2017: 6 · 2016: 16 · 2015: 14 · 2014: 12 · 2013: 9
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Kr1477/10-3)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- microglia, alternative activation, M2 microglia, IL-4, Ym1, MAPK signaling, anti-inflammatory cytokines, neuroinflammation, neurodegenerative diseases
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Arginase, beta-N-Acetylhexosaminidases, Brain, Cells, Cultured, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Mice, Inbred C57BL, Receptors, Cell Surface, RNA, Messenger, Signal Transduction, Interleukin-4, Up-Regulation, Cytokines, Transforming Growth Factor beta, Microglia, Mitogen-Activated Protein Kinases, Lectins, Mice, Interleukin-4 Receptor alpha Subunit
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
