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.
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Microglia and astrocytes coordinate their functions in many ways, both in the healthy and diseased brain.
“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]
The Introduction reports that IL-33 released after CNS injury acts on both astrocytes and microglia to induce chemokines, supporting an example of their coordinated response to injury. It reports IL-33 expression in the healthy brain, but not coordinated functions there, and does not establish that the two cell types coordinate in many ways. No page number is available in our copy. (LLM, conf=0.84)
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“To address the role of IL-33 in recovery from CNS trauma, we subjected IL-33 and wild-type (WT) mice to an optic nerve crush injury (Yoles and Schwartz, 1998), a model that is dependent on immune assistance for optimal neuronal survival (Kipnis et al., 2004; Walsh et al., 2015).”
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BackgroundImmune‐related mechanisms participating in resistance and susceptibility to glutamate toxicity
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“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).”
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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 240 · see citing works
“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 241 · see citing works
“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 239 · see citing works
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 · see citing works
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 218 · see citing works
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 · see citing works
ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury
Yang, Y.-Y., Liu, H., Zhang, H., Ye, Q., Wang, J.-Y., Yang, B.-Y., Mao, L.-L., Zhu, W., Leak, R., Xiao, B., et al. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3233-16.2017 · Cited by 188 · see citing works
“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 218 · see citing works
“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 190 · see citing works
“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 186 · see citing works
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 · see citing works
“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., Cui, Y., Kim, H., Thi, A. H. L., Choi, J.-Y., Kim, E. Y., Hwang, D., & Kim, B. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1924-15.2015 · Cited by 160 · see citing works
“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 161 · see citing works
“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 165 · see citing works
“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 167 · see citing works
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 156 · see citing works
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 148 · see citing works
Self-citationRegulatory T cells and skeletal muscle regeneration
Schiaffino, S., Pereira, M. G., Ciciliot, S., & Rovere-Querini, P. (2017) · The FEBS Journal · doi:10.1111/febs.13827 · Cited by 136 · see citing works
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 · see citing works
“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 142 · see citing works
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 133 · see citing works
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 · see citing works
“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 · see citing works
“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 117 · see citing works
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 117 · see citing works
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 111 · see citing works
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 104 · see citing works
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 98 · see citing works
“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 100 · see citing works
“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 101 · see citing works
“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 99 · see citing works
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 · see citing works
“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 · see citing works
“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 91 · see citing works
“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 97 · see citing works
“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 86 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 97 · see citing works
“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 89 · see citing works
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 94 · see citing works
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 79 · see citing works
“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 72 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
Kempuraj, D., Thangavel, R., Selvakumar, G., Ahmed, M. E., Zaheer, S. A., Raikwar, S., Zahoor, H., Saeed, D., Dubova, I., Giler, G. E., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1177-7 · Cited by 63 · see citing works
“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., & Krebs, P. (2022) · Cytokine · doi:10.1016/j.cyto.2022.155961 · Cited by 62 · see citing works
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 67 · see citing works
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 · see citing works
Hu, Y., & Tao, W. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.01.006 · Cited by 61 · see citing works
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 62 · see citing works
“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 72 · see citing works
Targeting IL-33/ST2 signaling: regulation of immune function and analgesia
Fattori, V., Hohmann, M., Rossaneis, A. C., Manchope, M. F., Alves-Filho, J., Cunha, T., Cunha, F., & Verri, W. (2017) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2017.1398734 · Cited by 61 · see citing works
“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 64 · see citing works
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 · see citing works
“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 · see citing works
“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 67 · see citing works
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 · see citing works
“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 65 · see citing works
“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 62 · see citing works
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 54 · see citing works
“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 63 · see citing works
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 56 · see citing works
Relja, B., Mörs, K., & Marzi, İ. (2018) · European Journal of Trauma and Emergency Surgery · doi:10.1007/s00068-018-0962-3 · Cited by 56 · see citing works
“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., Zhang, M.-Y., Wang, T., Fan, Y.-Y., Yu, L.-S., Ye, G.-H., Wang, Z., Gao, C., Wang, H.-C., Luo, C.-L., et al. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00095 · Cited by 53
“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 · see citing works
“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 · see citing works
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 60 · see citing works
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 · see citing works
“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
- 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 › 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 ›
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