Abstract
Neuroinflammation plays critical roles in multiple sclerosis (MS). In addition to the part played by the lymphocytes, the underlying mechanisms could, in part, be also attributed to activation mediated by astrocytes. Macrophage inflammatory protein-1α (MIP-1α) has been implicated in a number of pathological conditions, specifically attributable to its potent chemottractant effects. Its modulation by IL-17, however, has received very little attention. In the present study, we demonstrated IL-17-mediated induction of MIP-1α in rat primary astroctyes through its binding to the cognate IL-17RA. Furthermore, this effect was mediated via the activation of Src, mitogen-activated protein kinases (MAPKs), PI3K/Akt and NF-kB pathways, culminating ultimately into increased expression of MIP-1α. Exposure of primary mouse astrocytes to IL-17 resulted in increased expression of glial fibrillary acidic protein and, this effect was abrogated in cells cultured in presence of the MIP-1α neutralizing antibody, thus underscoring its role in the activation of astrocytes. In vivo relevance of these findings was further corroborated in experimental autoimmune encephalomyelitis mice that demonstrated significantly increased activation of astrocytes with concomitant increased expression of MIP-1α in the corpus callosum compared with control group. Understanding the regulation of MIP-1α expression may provide insights into the development of potential therapeutic targets for neuroinflammation associated with multiple sclerosis.
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06 October 2020
A Correction to this paper has been published: https://doi.org/10.1007/s11481-020-09962-3
References
Allen NJ, Barres BA (2009) Neuroscience: glia - more than just brain glue. Nature 457:675–677
Altuntas CZ, Daneshgari F, Liu G, Fabiyi A, Kavran M, Johnson JM, Gulen MF, Jaini R, Li X, Frenkl TL, Tuohy VK (2008) Bladder dysfunction in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 203:58–63
Calderon TM, Eugenin EA, Lopez L, Kumar SS, Hesselgesser J, Raine CS, Berman JW (2006) A role for CXCL12 (SDF-1alpha) in the pathogenesis of multiple sclerosis: regulation of CXCL12 expression in astrocytes by soluble myelin basic protein. J Neuroimmunol 177:27–39
Choi JS, Kim HY, Chung JW, Chun MH, Kim SY, Yoon SH, Lee MY (2005) Activation of Src tyrosine kinase in microglia in the rat hippocampus following transient forebrain ischemia. Neurosci Lett 380:1–5
Cortez DM, Feldman MD, Mummidi S, Valente AJ, Steffensen B, Vincenti M, Barnes JL, Chandrasekar B (2007) IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1/2-dependent C/EBP-beta, NF-kappaB, and AP-1 activation. Am J Physiol Heart Circ Physiol 293:H3356–H3365
Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190
Elain G, Jeanneau K, Rutkowska A, Mir AK, Dev KK (2014) The selective anti-IL17A monoclonal antibody secukinumab (AIN457) attenuates IL17A-induced levels of IL6 in human astrocytes. Glia 62:725–735
Fuller ML, DeChant AK, Rothstein B, Caprariello A, Wang R, Hall AK, Miller RH (2007) Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Ann Neurol 62:288–300
Greenberg BM, Calabresi PA (2008) Future research directions in multiple sclerosis therapies. Semin Neurol 28:121–127
Haddjeri N, de Montigny C, Blier P (1997) Modulation of the firing activity of noradrenergic neurones in the rat locus coeruleus by the 5-hydroxtryptamine system. Br J Pharmacol 120:865–875
Hsieh HG, Loong CC, Lin CY (2002) Interleukin-17 induces src/MAPK cascades activation in human renal epithelial cells. Cytokine 19:159–174
Huang H, Kim HJ, Chang EJ, Lee ZH, Hwang SJ, Kim HM, Lee Y, Kim HH (2009) IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ 16:1332–1343
Huang W, Rha GB, Chen L, Seelbach MJ, Zhang B, Andras IE, Bruemmer D, Hennig B, Toborek M (2010) Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial migration of HIV-1-infected cells. Am J Physiol Heart Circ Physiol 298:H1136–H1145
Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376
Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K, Li X (2002) Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol 22:7158–7167
Kang Z, Altuntas CZ, Gulen MF, Liu C, Giltiay N, Qin H, Liu L, Qian W, Ransohoff RM, Bergmann C, Stohlman S, Tuohy VK, Li X (2010) Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32:414–425
Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD (1995) An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 155:5003–5010
Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med 13:1173–1175
Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467–476
Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573
Krakowski ML, Owens T (2000) Naive T lymphocytes traffic to inflamed central nervous system, but require antigen recognition for activation. Eur J Immunol 30:1002–1009
Luo Q, Sun Y, Gong FY, Liu W, Zheng W, Shen Y, Hua ZC, Feng GS, Xu Q (2013) Blocking initial infiltration of pioneer CD8 T cells into the CNS via inhibition of SHP-2 ameliorates experimental autoimmune encephalomyelitis in mice. Br J Pharmacol. doi:10.1111/bph.12565
Ma X, Reynolds SL, Baker BJ, Li X, Benveniste EN, Qin H (2010) IL-17 enhancement of the IL-6 signaling cascade in astrocytes. J Immunol 184:4898–4906
Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H (1999) Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 5:101–104
Meares GP, Ma X, Qin H, Benveniste EN (2012) Regulation of CCL20 expression in astrocytes by IL-6 and IL-17. Glia 60:771–781
Meucci O, Fatatis A, Simen AA, Miller RJ (2000) Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci U S A 97:8075–8080
Nair A, Frederick TJ, Miller SD (2008) Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci 65:2702–2720
Nash B, Ioannidou K, Barnett SC (2011) Astrocyte phenotypes and their relationship to myelination. J Anat 219:44–52
Oba Y, Lee JW, Ehrlich LA, Chung HY, Jelinek DF, Callander NS, Horuk R, Choi SJ, Roodman GD (2005) MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Exp Hematol 33:272–278
Oksenberg JR, Seboun E, Hauser SL (1996) Genetics of demyelinating diseases. Brain Pathol 6:289–302
Peterson LK, Fujinami RS (2007) Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol 184:37–44
Pincheira R, Castro AF, Ozes ON, Idumalla PS, Donner DB (2008) Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signaling pathways that regulate transcription factor activity. J Immunol 181:1288–1298
Potula R, Dhillion N, Sui Y, Zien CA, Funa K, Pinson D, Mayo MS, Singh DK, Narayan O, Buch S (2004) Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis. Am J Pathol 165:815–824
Qian Y, Zhao Z, Jiang Z, Li X (2002) Role of NF kappa B activator Act1 in CD40-mediated signaling in epithelial cells. Proc Natl Acad Sci U S A 99:9386–9391
Rahman MS, Yamasaki A, Yang J, Shan L, Halayko AJ, Gounni AS (2006) IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: role of MAPK (Erk1/2, JNK, and p38) pathways. J Immunol 177:4064–4071
Rodgers JM, Zhou L, Miller SD (2010) Act1, scene brain: astrocytes play a lead role. Immunity 32:302–304
Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647
Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35
Song X, Tanaka S, Cox D, Lee SC (2004) Fcgamma receptor signaling in primary human microglia: differential roles of PI-3 K and Ras/ERK MAPK pathways in phagocytosis and chemokine induction. J Leukoc Biol 75:1147–1155
Tanabe S, Heesen M, Berman MA, Fischer MB, Yoshizawa I, Luo Y, Dorf ME (1997) Murine astrocytes express a functional chemokine receptor. J Neurosci 17:6522–6528
Tarassishin L, Suh HS, Lee SC (2014) LPS and IL-1 differentially activate mouse and human astrocytes: role of CD14. Glia 62:999–1013
Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172:146–155
Williams A, Piaton G, Lubetzki C (2007) Astrocytes–friends or foes in multiple sclerosis? Glia 55:1300–1312
Wilson EH, Weninger W, Hunter CA (2010) Trafficking of immune cells in the central nervous system. J Clin Invest 120:1368–1379
Yan Y, Ding X, Li K, Ciric B, Wu S, Xu H, Gran B, Rostami A, Zhang GX (2012) CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes. Mol Ther 20:1338–1348
Yao H, Peng F, Dhillon N, Callen S, Bokhari S, Stehno-Bittel L, Ahmad SO, Wang JQ, Buch S (2009) Involvement of TRPC channels in CCL2-mediated neuroprotection against tat toxicity. J Neurosci 29:1657–1669
Zhu L, Wu Y, Wei H, Xing X, Zhan N, Xiong H, Peng B (2011) IL-17R activation of human periodontal ligament fibroblasts induces IL-23 p19 production: Differential involvement of NF-kappaB versus JNK/AP-1 pathways. Mol Immunol 48:647–656
Zimmermann J, Krauthausen M, Hofer MJ, Heneka MT, Campbell IL, Muller M (2013) CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia. PLoS One 8:e57307
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (No. 81322048), Award for Jiangsu Specially Appointed Professor and the Major State Basic Research Development Program of China (973 Program) (2013CB733800, 2013CB733803).
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The authors declare no competing financial interests.
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Hongwei Yi and Ying Bai contributed equally to the work
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Yi, H., Bai, Y., Zhu, X. et al. IL-17A Induces MIP-1α Expression in Primary Astrocytes via Src/MAPK/PI3K/NF-kB Pathways: Implications for Multiple Sclerosis. J Neuroimmune Pharmacol 9, 629–641 (2014). https://doi.org/10.1007/s11481-014-9553-1
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DOI: https://doi.org/10.1007/s11481-014-9553-1