The DOI matches its Crossref record; 30 of the 34 references it cites were found in a registry or an index.
The Glia-Derived Alarmin IL-33 Orchestrates the Immune Response and Promotes Recovery following CNS Injury
Open accessAbstract
Inflammation is a prominent feature of CNS injury that heavily influences neuronal survival, yet the signals that initiate and control it remain poorly understood. Here we identify the nuclear alarmin, interleukin (IL)-33, as an important regulator of the innate immune response after CNS injury. IL-33 is expressed widely throughout the healthy brain and is concentrated in white mater due to predominant expression in post-mitotic oligodendrocytes. IL-33 is released immediately after CNS injury from damaged oligodendrocytes, acting on local astrocytes and microglia to induce chemokines critical for monocyte recruitment. Mice lacking IL-33 have impaired recovery after CNS injury, which is associated with reduced myeloid cell infiltrates and decreased induction of M2 genes at the injury site. These results demonstrate a novel molecular mediator contributing to immune cell recruitment to the injured CNS and may lead to new therapeutic insights in CNS injury and neurodegenerative diseases.
Overview
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
Verification
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, recent data indicate that microglia and astrocytes coordinate their functions in many ways, both in the healthy and diseased brain [14–21].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [15]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Schmitz, J., Owyang, A. M., Oldham, E. R., Song, Y., Murphy, E., McClanahan, T. K., Zurawski, G., Moshrefi, M., Qin, J., Li, X., et al. (2005) · Immunity · doi:10.1016/j.immuni.2005.09.015 · Cited by 3,773 · cited 3×
“A potential explanation of these dual aspects is macrophage phenotype, with the alternative (M2) and classical (M1) polarization correlating with beneficial or detrimental responses, respectively (Kigerl et al., 2009; Kroner et al., 2014; Schmitz et al., 2005; Shechter et al., 2009, 2013).”
Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129 · cited 2×
“Costaining of IL-33 with the astrocyte marker ALDH1L1 (Cahoy et al., 2008) demonstrated that these cells were astrocytes, which express IL-33 in gray matter regions (i.e., neocortex) but not in white matter (i.e., corpus callosum ; Figures 1F and 1G).”
Kigerl, K. A., Gensel, J. C., Ankeny, D. P., Alexander, J. K., Donnelly, D. J., & Popovich, P. G. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3257-09.2009 · Cited by 2,130 · cited 2×
“A potential explanation of these dual aspects is macrophage phenotype, with the alternative (M2) and classical (M1) polarization correlating with beneficial or detrimental responses , respectively (Kigerl et al., 2009; Kroner et al., 2014; Schmitz et al., 2005; Shechter et al., 2009, 2013).”
Basso, D., Fisher, L., Anderson, A., Jakeman, L., McTigue, D. M., & Popovich, P. (2006) · Journal of Neurotrauma · doi:10.1089/neu.2006.23.635 · Cited by 1,615 · cited 2×
“Error bars represent mean ± SEM; *p % 0.05; **p % 0.01; ***p % 0.001. relative to WT counterparts after SCI, as assessed by Basso mouse scale (Basso et al., 2006 ) (Figure 3E).”
InfluentialDisease-associated functions of IL-33: the new kid in the IL-1 family
Liew, F. Y., Pitman, N. I., & McInnes, I. B. (2010) · Nature reviews. Immunology · doi:10.1038/nri2692 · Cited by 1,020 · cited 2×
“Interleukin (IL)-33 is a nuclear alarmin of the IL-1 cytokine family released by cell damage and is well characterized as an immune activator in conditions such as asthma (Liew et al., 2010), allergy (Oboki et al., 2010), and sepsis (Alves-Filho et al., 2010).”
Neuronal and Glial Apoptosis after Traumatic Spinal Cord Injury
Liu, X. Z., Xu, X. M., Hu, R., Du, C., Zhang, S. X., McDonald, J. W., Dong, H. X., Wu, Y. J., Fan, G. S., Jacquin, M. F., et al. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-14-05395.1997 · Cited by 770 · cited 1×
“Neurons and glia directly damaged by the initial insult die, both necrotically and apoptotically (Grossman et al., 2001; Liu et al., 1997; Lytle and Wrathall, 2007), followed by secondary degeneration—a spread of damage through apoptotic death of initially uninjured neurons (Dusart and Schwab,…”
Shechter, R., London, A., Varol, C., Raposo, C., Cusimano, M., Yovel, G., Rolls, A., Mack, M., Pluchino, S., Martino, G., et al. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000113 · Cited by 770 · cited 1×
“A potential explanation of these dual aspects is macrophage phenotype, with the alternative (M2) and classical (M1) polarization correlating with beneficial or detrimental responses, respectively (Kigerl et al., 2009; Kroner et al., 2014; Schmitz et al., 2005; Shechter et al., 2009, 2013).”
BackgroundKurowska‐Stolarska, M., Stolarski, B., Kewin, P., Murphy, G., Corrigan, C. J., Ying, S., Pitman, N. I., Mirchandani, A. S., Rana, B. M. J., van Rooijen, N., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901575 · Cited by 747 · cited 1×
“Given previous reports showing that IL-33 can polarize toward an ‘‘M2’’ (IL-4-activated) macrophage skew (Kurowska-Stolarska et al., 2009) and that M2 macrophages promote neuronal survival (Kigerl et al.”
BackgroundShechter, R., Miller, O., Yovel, G., Rosenzweig, N., London, A., Ruckh, J., Kim, K.-W., Klein, E., Kalchenko, V., Bendel, P., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.012 · Cited by 683 · cited 2×
“The overall impact of this immune response remains debated, as it has potential to drive both beneficial (Shechter et al., 2013; Walsh et al., 2015; Walsh et al., 2014) and detrimental (Evans et al., 2014; Kroner et al., 2014) effects on recovery.”
Suppression of Interleukin-33 Bioactivity through Proteolysis by Apoptotic Caspases
Lüthi, A. U., Cullen, S. P., McNeela, E. A., Duriez, P. J., Afonina, I. S., Sheridan, C., Brumatti, G., Taylor, R. C., Kersse, K., Vandenabeele, P., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.05.007 · Cited by 677 · cited 1×
“Upon release from necrotically dying cells (Lüthi et al., 2009), IL-33 binds IL-33R, a heterodimer of IL-1RAcP and ST2, and initiates an intracellular cascade involving MyD88 and NFkB (Liew et al.”
Flagged first, then by citations
4 of the 34 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Levkovitch-Verbin, 2000, RGC death in mice after optic nerve crush injury: oxidative stress and neuroprotection, Invest. Ophthalmol. Vis. Sci., 41, 4169
Cited by
Sorted by citations
Interactions between the microbiota, immune and nervous systems in health and disease
Fung, T. C., Olson, C. A., & Hsiao, E. Y. (2017) · Nature Neuroscience · doi:10.1038/nn.4476 · Cited by 1,900
The far-reaching scope of neuroinflammation after traumatic brain injury
Simon, D. W., McGeachy, M. J., Bayır, H., Clark, R. S. B., Loane, D. J., & Kochanek, P. M. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.13 · Cited by 1,190
Interleukin-33 in health and disease
Liew, F. Y., Girard, J., & Turnquist, H. R. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.95 · Cited by 1,178
Interleukin‐33 ( IL ‐33): A nuclear cytokine from the IL ‐1 family
Cayrol, C., & Girard, J. (2017) · Immunological Reviews · doi:10.1111/imr.12619 · Cited by 913
The Biology of Regeneration Failure and Success After Spinal Cord Injury
Tran, A. P., Warren, P. M., & Silver, J. (2018) · Physiological Reviews · doi:10.1152/physrev.00017.2017 · Cited by 903
“Soon thereafter, they adopt an amoeboid shape (415) before migrating to the lesion area in response to alarmins such as IL-33, IL-1B, and TNF- released as soon as 15 min after the lesion (127, 323).”
BackgroundResultInfluentialMacrophages in health and disease
Park, M. D., Silvin, A., Ginhoux, F., & Merad, M. (2022) · Cell · doi:10.1016/j.cell.2022.10.007 · Cited by 644
Vainchtein, I. D., Chin, G., Cho, F. S., Kelley, K. W., Miller, J. G., Chien, E. C., Liddelow, S. A., Nguyen, P. T., Nakao-Inoue, H., Dorman, L. C., et al. (2018) · Science · doi:10.1126/science.aal3589 · Cited by 657
Mechanisms of Organ Injury and Repair by Macrophages
Vannella, K. M., & Wynn, T. A. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034356 · Cited by 656
Cytokine networks in neuroinflammation
Becher, B., Spath, S., & Goverman, J. M. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.123 · Cited by 707
Kuswanto, W. F., Burzyn, D., Panduro, M., Wang, K. K., Jang, Y. C., Wagers, A. J., Benoist, C. O., & Mathis, D. J. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.009 · Cited by 529
“It might also be worth noting that as many as 1/3 of dispersed brain cells, especially oligodendrocytes and gray-matter astrocytes, were reported to express IL-33, which is released from injured central nervous system (CNS) tissue and promotes recovery after CNS injury (Gadani et al., 2015).”
The Meningeal Lymphatic System: A New Player in Neurophysiology
Da Mesquita, S., Fu, Z., & Kipnis, J. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.022 · Cited by 479
Self-citationAstrocytes and microglia: In sickness and in health
Vainchtein, I. D., & Molofsky, A. V. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.01.003 · Cited by 450
“As an alarmin, one of IL-33’s most potent effects is to robustly increase chemokine expression in microglia and drive recruitment of peripheral macrophages into the brain [78].”
BackgroundMolofsky, A. B., Gool, F. V., Liang, H.-E., Dyken, S. J. V., Nussbaum, J. C., Lee, J., Bluestone, J. A., & Locksley, R. M. (2015) · Immunity · doi:10.1016/j.immuni.2015.05.019 · Cited by 451
“…July 21, 2015 ª2015 Elsevier Inc. 161 resolution of tissue damage in models of colitis (Duan et al., 2012; Schiering et al., 2014), hepatitis (Liang et al., 2013), cutaneous wounding (Yin et al., 2013), central nervous system injury (Gadani et al., 2015), and atherosclerosis (Miller et al., 2008).”
BackgroundInterleukin 33 is a guardian of barriers and a local alarmin
Martin, N. T., & Martin, M. U. (2016) · Nature Immunology · doi:10.1038/ni.3370 · Cited by 422
Multifaceted interactions between adaptive immunity and the central nervous system
Kipnis, J. (2016) · Science · doi:10.1126/science.aag2638 · Cited by 376
Self-citationIL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
Fu, A. K. Y., Hung, K.-W., Yuen, M. Y. F., Zhou, X., Mak, D. S. Y., Chan, I. C. W., Cheung, T. H., Zhang, B., Fu, W.-Y., Liew, F. Y., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604032113 · Cited by 369
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 411
Dealing with danger in the CNS: the response of the immune system to injury
Gadani, S. P., Walsh, J. T., Lukens, J. R., & Kipnis, J. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.019 · Cited by 342
Self-citationSun, G., Li, G., Li, D., Huang, W., Zhang, R., Zhang, H., Duan, Y., & Wang, B. (2018) · Materials Science and Engineering C · doi:10.1016/j.msec.2018.04.006 · Cited by 314
Myeloid Cells in the Central Nervous System
Herz, J., Filiano, A. J., Wiltbank, A. T., Yogev, N., & Kipnis, J. (2017) · Immunity · doi:10.1016/j.immuni.2017.06.007 · Cited by 345
“We have recently demonstrated the presence of type 2 innate lymphoid cells (ILC2s) within meningeal tissue (Gadani et al., 2017).”
BackgroundSelf-citationCayrol, C., & Girard, J. (2022) · Cytokine · doi:10.1016/j.cyto.2022.155891 · Cited by 350
Immune cells and CNS physiology: Microglia and beyond
Norris, G. T., & Kipnis, J. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20180199 · Cited by 274
“The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury.”
BackgroundInfluentialSelf-citationRole and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage
Zhu, H., Wang, Z., Yu, J., Yang, X., He, F., Liu, Z., Che, F., Chen, X., Ren, H., Hong, M., et al. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.03.003 · Cited by 329
Barcoded viral tracing of single-cell interactions in central nervous system inflammation
Clark, I. C., Gutiérrez-Vázquez, C., Wheeler, M. A., Li, Z., Rothhammer, V., Linnerbauer, M., Sanmarco, L. M., Guo, L., Blain, M., Zandee, S. E. J., et al. (2021) · Science · doi:10.1126/science.abf1230 · Cited by 285
“S. P. Gadani, J. T. Walsh, I. Smirnov, J. Zheng, J. Kipnis, The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury.”
BackgroundRegulatory T-Cells: Potential Regulator of Tissue Repair and Regeneration
Li, J., Tan, J. L., Martino, M. M., & Lui, K. O. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00585 · Cited by 354
“Nevertheless, IL-33 has been shown to facilitate recovery after CNS injury (58) and to drive accumulation of Treg in visceral adipose tissue of lean mice (59) and damaged muscle in young mice (60).”
BackgroundA shared disease-associated oligodendrocyte signature among multiple CNS pathologies
Kenigsbuch, M., Bost, P., Halevi, S., Chang, Y., Chen, S., Ma, Q., Hajbi, R., Schwikowski, B., Bodenmiller, B., Fu, H., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01104-7 · Cited by 233
Rostami, J., Mothes, T., Kolahdouzan, M., Eriksson, O., Moslem, M., Bergström, J., Ingelsson, M., O’Callaghan, P., Healy, L. M., Falk, A., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02158-3 · Cited by 224
Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders
Zengeler, K. E., & Lukens, J. R. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-020-00487-7 · Cited by 264
Mast cells in neuroinflammation and brain disorders
Hendriksen, E., van Bergeijk, D. A., Oosting, R. S., & Redegeld, F. A. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.001 · Cited by 249
“IL-6 can induce IL-13 release from mast cells and a ff ect expression of TLR2/TLR4 (Skaper et al., 2014a; Pietrzak et al., 2011; Zhang et al., 2010a), while TNF-α can upregulate PAR2 expression on mast cells augmenting PAR2 mediated mast cell activation and degranulation (Zhang et al., 2010c).”
InfluentialNeuroinflammation: An astrocyte perspective
Lee, H., Lee, J.-H., Flausino, L. E., & Quintana, F. J. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi7828 · Cited by 253
“However, astro-cyte-derived CCL2 can also recruit macrophages that promote tissue repair ( 136 ), suggesting that astrocytes can promote both proinflammatory and repair mechanisms in a context-specific manner.”
BackgroundOligodendrocyte lineage cells and depression
Zhou, B., Zhu, Z., Ransom, B. R., & Tong, X. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00930-0 · Cited by 245
How and why do T cells and their derived cytokines affect the injured and healthy brain?
Filiano, A. J., Gadani, S. P., & Kipnis, J. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.39 · Cited by 199
Self-citationThe role of the immune system in Alzheimer disease: Etiology and treatment
Jevtic, S. D., Sengar, A. S., Salter, M. W., & McLaurin, J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.005 · Cited by 224
The benefits of neuroinflammation for the repair of the injured central nervous system
Yong, H. Y. F., Rawji, K. S., Ghorbani, S., Xue, M., & Yong, V. W. (2019) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0223-3 · Cited by 190
ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury
Yang, Y., Liu, H., Zhang, H., Ye, Q., Wang, J., Yang, B., Mao, L., Zhu, W., Leak, R. K., Xiao, B., et al. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3233-16.2017 · Cited by 217
“Recent studies show that CNS damage can trigger the release of IL-33 from injured brain cells—mainly oligodendrocytes (OLs) and astrocytes (Gadani et al., 2015).”
BackgroundInfluentialDamage-associated molecular patterns in trauma
Relja, B., & Land, W. G. (2019) · European Journal of Trauma and Emergency Surgery · doi:10.1007/s00068-019-01235-w · Cited by 225
“Immediately after CNS injury IL-33 was released from damaged oligodendrocytes, acting on local astrocytes and microglia to induce chemokines critical for monocyte recruitment [173].”
BackgroundInfluentialSzebeni, G. J., Vízler, C., Kitajka, K., & Puskás, L. G. (2017) · Mediators of Inflammation · doi:10.1155/2017/9294018 · Cited by 195
“ily, is associated withTh2 and M2 polarization [30].”
New insights into glial scar formation after spinal cord injury
Tran, A. P., Warren, P. M., & Silver, J. (2021) · Cell and Tissue Research · doi:10.1007/s00441-021-03477-w · Cited by 188
Systematic Review of the Neurobiological Relevance of Chemokines to Psychiatric Disorders
Stuart, M. J., Singhal, G., & Baune, B. T. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00357 · Cited by 163
“Moreover, IL-33 released from damaged oligodendrocytes during CNS injury has recently been shown to induce expression of monocyte attracting chemokines, such as CCL2 and CXCL10, on local astrocytes and microglia (Gadani et al., 2015).”
BackgroundKwon, M. J., Shin, H. Y., Cui, Y., Kim, H., Thi, A. H. L., Choi, J. Y., Kim, E. Y., Hwang, D. H., & Kim, B. G. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1924-15.2015 · Cited by 188
“CCL2 can polarize macrophages to acquire M2 phenotypes in non-neural environments (Sierra-Filardi et al., 2014; Lee et al., 2015), as well as in the contused spinal cord (Gadani et al., 2015).”
BackgroundSpinal cord oligodendrocyte‐derived alarmin IL‐33 mediates neuropathic pain
Zarpelon, A. C., Rodrigues, F. C., Lopes, A. H., de Souza, G. R., de Carvalho, T. T., Pinto, L. G., Xu, D., Ferreira, S. H., Alves-Filho, J. C., McInnes, I. B., et al. (2015) · The FASEB Journal · doi:10.1096/fj.14-267146 · Cited by 168
“The IL-33 deficiency resulted in impaired CNS recovery after spinal cord injury due to lessened M2 response (30).”
BackgroundMechanisms of Endogenous Neuroprotective Effects of Astrocytes in Brain Injury
Bylicky, M. A., Mueller, G. P., & Day, R. M. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/6501031 · Cited by 170
“protecting healthy tissue from inflammatory consequences of white blood cell invasion [56, 212, 213].”
He, D., Xu, H., Zhang, H., Tang, R., Lan, Y., Xing, R., Li, S., Christian, E., Hou, Y., Lorello, P. J., et al. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.001 · Cited by 174
Interleukin-33 Promotes Serotonin Release from Enterochromaffin Cells for Intestinal Homeostasis
Chen, Z., Luo, J., Li, J., Kim, G., Stewart, A., Urban, J. F., Huang, Y., Chen, S., Wu, L., Chesler, A. T., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.10.014 · Cited by 162
Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury
Gadani, S. P., Smirnov, I., Wiltbank, A. T., Overall, C. C., & Kipnis, J. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20161982 · Cited by 152
Self-citationRegulatory T cells and skeletal muscle regeneration
Schiaffino, S., Pereira, M. G., Ciciliot, S., & Rovere, P. Q. (2016) · FEBS Journal · doi:10.1111/febs.13827 · Cited by 159
Jiang, M., Liu, X., Zhang, D., Wang, Y., Hu, X., Xu, F., Jin, M., Cao, F., & Xu, L. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1124-6 · Cited by 139
“Recent studies have shown that IL-33 is released from CNS cells rapidly after injury and contributes to the activation of immune responses in lesion areas [28].”
Distal Consequences of Oral Inflammation
Konkel, J. E., O’Boyle, C., & Krishnan, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01403 · Cited by 144
The immune system and psychiatric disease: a basic science perspective
Bennett, F. C., & Molofsky, A. V. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13334 · Cited by 141
Lau, S.-F., Chen, C., Fu, W.-Y., Qu, J. Y., Cheung, T. H., Fu, A. K. Y., & Ip, N. Y. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107530 · Cited by 114
“The expression of ST2 is regulated in different cellular injury conditions, either through the negativefeedbackmechanism triggered by IL-33 or through the alteration of the proteasomal-dependent degradation pathway (Ciechanover and Kwon, 2015; Gadani et al., 2015; Zhao et al., 2012).”
BackgroundNeuronal integrity and complement control synaptic material clearance by microglia after CNS injury
Norris, G. T., Smirnov, I., Filiano, A. J., Shadowen, H. M., Cody, K. R., Thompson, J. A., Harris, T. H., Gaultier, A., Overall, C. C., & Kipnis, J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20172244 · Cited by 109
“Our laboratory and others have used crush injury of the optic nerve as a model to study neurodegeneration and neuroprotection, in both of which the immune system is a key player (Moalem et al., 1999; Schwartz and Cohen, 2000; Schwartz, 2004; London et al., 2011; Walsh et al., 2014, 2015; Gadani et al., 2015; Benhar et…”
MethodSelf-citationDroplet-based forward genetic screening of astrocyte–microglia cross-talk
Wheeler, M. A., Clark, I. C., Lee, H., Li, Z., Linnerbauer, M., Rone, J. M., Blain, M., Akl, C. F., Piester, G., Giovannoni, F., et al. (2023) · Science · doi:10.1126/science.abq4822 · Cited by 125
Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility
Russi, A. E., Ebel, M. E., Yang, Y., & Brown, M. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710401115 · Cited by 123
Adult oligodendrocyte progenitor cells – Multifaceted regulators of the CNS in health and disease
Fernández-Castañeda, A., & Gaultier, A. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.01.005 · Cited by 117
Ravanetti, L., Dijkhuis, A., Dekker, T., Piñeros, Y. S. S., Ravi, A., Dierdorp, B., Erjefalt, J. S., Mori, M., Pavlidis, S. P., Adcock, I. M., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.08.051 · Cited by 107
Therapeutics targeting the inflammasome after central nervous system injury
Vaccari, J. P. D. R., Dietrich, W. D., & Keane, R. W. (2015) · Translational research · doi:10.1016/j.trsl.2015.05.003 · Cited by 99
“In the CNS, IL-33 is present in oligodendrocytes and when secreted it acts on microglia and astrocytes to induce recruitment of monocytes.(18) After injury, IL-33 is responsible for the recruitment of M2 macrophages.”
Fairlie‐Clarke, K. J., Barbour, M., Wilson, C., Hridi, S. U., Allan, D., & Jiang, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02596 · Cited by 101
“In contrast to its abundant expression in the white matter region in brain (12), IL-33 immune reactivity is prominent in spinal cord gray matter and significantly lower in the white matter (29).”
BackgroundInfluentialCayrol, C. (2021) · Cells · doi:10.3390/cells11010107 · Cited by 104
“In this model, IL-33 released from mature oligodendrocytes was shown to drive chemokine production from ST2+ astrocytes critical for monocyte recruitment and repair after central nervous system (CNS) injury [30].”
MethodEndogenous IL-33 Contributes to Kidney Ischemia-Reperfusion Injury as an Alarmin
Ferhat, M., Robin, A., Giraud, S., Sena, S., Goujon, J., Touchard, G., Hauet, T., Girard, J., Gombert, J., Herbelin, A., et al. (2018) · Journal of the American Society of Nephrology · doi:10.1681/asn.2017060650 · Cited by 101
IL-33 amplifies an innate immune response in the degenerating retina
Xi, H., Katschke, K. J., Li, Y., Truong, T., Lee, W. P., Diehl, L. J., Rangell, L. K., Tao, J., Arceo, R., Eastham‐Anderson, J., et al. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20150894 · Cited by 93
“In models of acute traumatic CNS injury, glia-derived IL-33 promotes myeloid cell infiltration and improves recovery of affected CNS tissue (Gadani et al., 2015).”
BackgroundHou, J., Zhou, Y., Cai, Z., Terekhova, M., Swain, A., Andhey, P. S., Guimaraes, R. M., Ulezko Antonova, A., Qiu, T., Sviben, S., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112293 · Cited by 85
“40,41 IL-33 was thought to be predominantly released by astrocytes, 42,43 especially in humans.”
Gautier, V., Cayrol, C., Farache, D., Roga, S., Monsarrat, B., Burlet‐Schiltz, O., de Peredo, A. G., & Girard, J. (2016) · Scientific Reports · doi:10.1038/srep34255 · Cited by 99
“IL-33 is constitutively expressed in the nuclei of producing cells during homeostasis, including epithelial cells from various barrier tissues, endothelial cells from blood vessels, fibroblastic reticular cells of lymphoid organs, and post-mitotic oligodendrocytes in the brain 21–24 .”
Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical synapse development
Xie, Y., Kuan, A. T., Wang, W., Herbert, Z. T., Mosto, O., Olukoya, O., Adam, M. A., Vu, S., Kim, M., Tran, D., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110416 · Cited by 98
“Previous research has shown that in the adult mouse CNS, Il33 is mainly expressed by oligodendrocytes (Gadani et al., 2015).”
Dagher, R., Copenhaver, A. M., Besnard, V., Berlin, A. A., Hamidi, F., Maret, M., Wang, J., Qu, X., Shrestha, Y., Wu, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18466-w · Cited by 89
Cao, K., Liao, X., Lü, J., Yao, S., Wu, F., Zhu, X., Shi, D., Wen, S., Liu, L., & Zhou, H. Y. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1169-6 · Cited by 84
“It has recently been reported that IL-33 exerts protective effects against hemorrhage and acute ischemic brain injury in animal models [26, 27].”
Zhang, J., Wang, P., Yan, Y., Li, Y., Guan, M., Yu, J., & Wang, X. (2017) · Oncology Reports · doi:10.3892/or.2017.5926 · Cited by 90
“and gray matter astrocytes, and released at sites of injury to promote recovery (23).”
BackgroundDas, S., Li, Z., Noori, A., Hyman, B. T., & Serrano-Pozo, A. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01898-y · Cited by 80
The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine
Fournié, J., & Poupot, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02506 · Cited by 99
“Full-length IL-33 is thus considered as an alarmin produced as a result of an injury to the central nervous system (15), a mechanical stress (17, 18), necroptosis (19) but also in pathological wound repair and fibrosis (20–22).”
BackgroundChen, L., Wang, W., Lin, Z., Lu, Y., Chen, H., Li, B., Li, Z., Xia, H., Li, L., & Zhang, T. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01396-8 · Cited by 76
“Macrophages begin to increase rapidly in the SCI part after 1–2 days due to the serious inflammatory [40].”
BackgroundReparative T lymphocytes in organ injury
D’Alessio, F. R., Kurzhagen, J. T., & Rabb, H. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124614 · Cited by 91
New insights into mononuclear phagocyte biology from the visual system
Reyes, N. S., O’Koren, E. G., & Saban, D. R. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.13 · Cited by 95
Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease
Matejuk, A., Vandenbark, A. A., & Offner, H. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.672455 · Cited by 81
“In the CNS injury model, the adaptive response follows the activation of glia and the release of IL-33, a monocyte recruitment cytokine most abundantly present in the nervous system and mice lacking IL-33 have impaired recovery after CNS injury, which is the consequence of reduced myeloid cell infiltrates (221).”
BackgroundExosomal MicroRNAs as Mediators of Cellular Interactions Between Cancer Cells and Macrophages
Kwon, Y., Kim, M.-S., Kim, Y., Jung, H. S., & Jeoung, D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01167 · Cited by 75
“IL-33, a cytokine of the IL-1family, is associated with Th2 and M2 polarization (31).”
BackgroundAllan, D., Fairlie‐Clarke, K. J., Elliott, C., Schuh, C., Barnett, S. C., Lassmann, H., Linington, C., & Jiang, H. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0344-1 · Cited by 77
“While several other studies confirmed the expression of IL-33 by murine oligodendrocytes [5, 11, 40], our observation of IL-33 and ST2 expression by oligodendrocytes in human CNS tissues support a role for IL-33/ST2 in CNS demyelination or remyelination.”
BackgroundResultTherapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases
Chen, W.-Y., Tsai, T.-H., Yang, J.-L., & Li, L.-C. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000492885 · Cited by 65
IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria
Reverchon, F., Mortaud, S., Sivoyon, M., Maillet, I., Laugeray, A., Palomo, J., Montécot, C., Herzine, A., Même, S., Même, W., et al. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006322 · Cited by 65
Kempuraj, D., Thangavel, R., Selvakumar, G. P., Ahmed, M. E., Zaheer, S. A., Raikwar, S. P., Zahoor, H., Saeed, D., Dubova, I., Giler, G., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1177-7 · Cited by 66
“Alarmin cytokine, IL-33, released from injured cells in the CNS acts on local microglia and astrocytes to release chemokine to attract immune cells into the site of injury to prevent further injury and inflammatory processes [53].”
BackgroundIL-33 biology in cancer: An update and future perspectives
Yeoh, W. J., Vu, V. P., & Krebs, P. (2022) · Cytokine · doi:10.1016/j.cyto.2022.155961 · Cited by 80
Bretheau, F., Castellanos-Molina, A., Bélanger, D., Kusik, M., Mailhot, B., Boisvert, A., Vallières, N., Lessard, M., Gunzer, M., Liu, X., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33463-x · Cited by 69
Regulatory T cell is critical for interleukin-33-mediated neuroprotection against stroke
Liu, X., Hu, R., Pei, L., Si, P., Wang, C., Tian, X., Wang, X., Liu, H., Wang, B., Xia, Z., et al. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113233 · Cited by 68
Hu, Y., & Tao, W. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.01.006 · Cited by 64
Divergent Roles for the IL-1 Family in Gastrointestinal Homeostasis and Inflammation
McEntee, C. P., Finlay, C. M., & Lavelle, E. C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01266 · Cited by 63
“Furthermore, IL-33 release following tissue damage in mice has been shown to be required for the initiation of effective wound healing (154, 155).”
BackgroundNeurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy
Rajchgot, T., Thomas, S. C., Wang, J.-C., Ahmadi, M., Balood, M., Crosson, T., Dias, J. P., Couture, R., Claing, A., & Talbot, S. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00025 · Cited by 74
Targeting IL-33/ST2 signaling: regulation of immune function and analgesia
Fattori, V., Hohmann, M. S., Rossaneis, A. C., Manchope, M. F., Alves-Filho, J. C., Cunha, T. M., Cunha, F. Q., & Verri, W. A., Jr. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1398734 · Cited by 60
“aureus-induced sepsis [22] Peritoneal macrophages [83] CIA [56] SCI [32] TNBS-induced colitis [86] DSS-induced colitis [86] IL-33 KO mouse SCI [32] siRNA ST2 In vitro (RAW264.”
InfluentialEngineered T cell therapy for central nervous system injury
Gao, W., Kim, M. W., Dykstra, T., Du, S., Boskovic, P., Lichti, C. F., Ruiz-Cardozo, M. A., Gu, X., Shapira, T. W., Rustenhoven, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07906-y · Cited by 71
Self-citationInterleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury
Wicher, G., Wallenquist, U., Lei, Y., Enoksson, M., Li, X.-F., Fuchs, B., Hamdeh, S. A., Marklund, N., Hillered, L., Nilsson, G., et al. (2017) · Journal of Neurotrauma · doi:10.1089/neu.2016.4900 · Cited by 60
“12 Moreover, Gadani and colleagues 12 found strongest expression of IL-33 in myelinated regions of the intact CNS, suggesting differences in the regulation and/or function of IL-33 in various regions of this system.”
Bormann, D., Knoflach, M., Poreba, E., Riedl, C. J., Testa, G., Orset, C., Levilly, A., Cottereau, A., Jauk, P., Hametner, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50465-z · Cited by 65
“Interest-ingly,both Vim and Il33 ,havepreviouslybeenshowntobeupregulated upon injury in various oligodendrocyte lineage cells 34,35 .”
Tackling the glial scar in spinal cord regeneration: new discoveries and future directions
Shafqat, A., Albalkhi, I., Magableh, H. M., Saleh, T., AlKattan, K. M., & Yaqinuddin, A. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1180825 · Cited by 71
Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation
Rao, X., Hua, F., Zhang, L., Lin, Y., Fang, P., Chen, S., Ying, J., & Wang, X. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03570-w · Cited by 64
“As a cytokine, IL-33 is upregulated and released upon inflammatory stimulation after injury and is thought to play roles in neuroinflammatory diseases via its binding to the ST2 receptor [6, 7, 31, 32].”
BackgroundType 2 immunity in the brain and brain borders
Mamuladze, T., & Kipnis, J. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01043-8 · Cited by 67
“Upon injury, IL-33 is released through an unknown mechanism and promotes monocyte recruitment to the injured site [35].”
BackgroundInfluentialSelf-citationIL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential
Sheng, F., Mi, L., Yu, J.-M., Yang, S., Zou, L., Yang, G., & Zhang, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1533335 · Cited by 71
TLR3 Agonist Poly-IC Induces IL-33 and Promotes Myelin Repair
Natarajan, C., Yao, S., & Sriram, S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152163 · Cited by 55
“In contrast to a recent study, we did not see constitutive expression of IL-33 in glial cells in normal animals [17].”
BackgroundResultDePaul, M. A., Palmer, M., Lang, B. T., Cutrone, R., Tran, A. P., Madalena, K. M., Bogaerts, A., Hamilton, J. A., Deans, R., Mays, R. W., et al. (2015) · Scientific Reports · doi:10.1038/srep16795 · Cited by 65
Regulation of neuroimmune processes by damage- and resolution-associated molecular patterns
Klegeris, A. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.293134 · Cited by 57
Relja, B., Mörs, K., & Marzi, İ. (2018) · European Journal of Trauma and Emergency Surgery · doi:10.1007/s00068-018-0962-3 · Cited by 57
“Furthermore, mice lacking IL-33 had impaired recovery after CNS injury, which is associated with reduced myeloid cell infiltrates and decreased induction of M2 genes at the injury site [143].”
BackgroundInfluentialGao, Y. Z., Zhang, M., Wang, T., Fan, Y., Yu, L., Ye, G.-H., Wang, Z., Gao, C., Wang, H., Luo, C., et al. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00095 · Cited by 62
“While most current findings indicate that IL-33 is expressed in neurons and oligodendrocytes, as well as in astrocytes and microglia (Gadani et al., 2015; Allan et al., 2016).”
BackgroundChen, H.-Z., Sun, Y. T., Lai, L., Wu, H., Xiao, Y., Ming, B., Gao, M., Zou, H., Xiong, P., Xu, Y., et al. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.09.019 · Cited by 55
“However, IL-33 has been reported to be expressed also in oligodendrocytes (Gadani et al., 2015) and endothelial cells (Yasuoka et al., 2011).”
Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria
Strangward, P., Haley, M., Albornoz, M. G., Barrington, J., Shaw, T. N., Dookie, R. S., Zeef, L. A. H., Baker, S. M., Winter, E., Tzeng, T.-C. J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801737115 · Cited by 60
Garnett, C. N., Watson, J. B., Higgins, E. K., Quan, N., & Bachstetter, A. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.688254 · Cited by 62
IL-33 deficiency causes persistent inflammation and severe neurodegeneration in retinal detachment
Augustine, J., Pavlou, S., Ali, I. H. A., Harkin, K., Ozaki, E., Campbell, M., Stitt, A. W., Xu, H.-P., & Chen, M. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1625-y · Cited by 50
“Mice lacking IL-33 have impaired recovery after CNS injury due to less myeloid cell, in particular, reparative M2 macrophage infiltration at the injury site [27].”
BackgroundResultInfluential
Metadata
- Authors
- Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J., & Kipnis, J.
- Affiliations
- University of Virginia (US)
- University of Virginia Medical Center (US)
- Corresponding author
- Gadani, Sachin P.
- Kipnis, Jonathan
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 85
- Issue
- 4
- Pages
- 703-709
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC12064979
- OpenAlex
- W2033591334
- Cited by
- 359
- References
- 34
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 28 · 2023: 35 · 2022: 35 · 2021: 46 · 2020: 39 · 2019: 32 · 2018: 37 · 2017: 24 · 2016: 18 · 2015: 11
- FWCI
- 16.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM007267)
- National Institute of Neurological Disorders and Stroke (NS061973, R01NS061973)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- IL-33, central nervous system injury, neuroinflammation, oligodendrocytes, astrocytes, microglia, monocyte recruitment, chemokines, myeloid cell infiltration, M2 macrophages, functional recovery, innate immune response
- MeSH terms
- Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, CX3C Chemokine Receptor 1, Animals, Animals, Newborn, Cells, Cultured, Central Nervous System Diseases, Disease Models, Animal, Female, Gene Expression Regulation, Interleukins, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neuroglia, Neurons, Retinal Ganglion Cells, Receptors, Interleukin, Ki-67 Antigen, Receptors, Chemokine, Recovery of Function, Green Fluorescent Proteins, Mice, In Vitro Techniques
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
