Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis

Abstract

BackgroundInterleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood.MethodsEAE was induced in C57Bl/6 mice by immunization with myelin oligodendroglial glycoprotein. IL-17RA expression in the CNS was compared between control and EAE mice using RT-PCR, in situ hybridization, and immunohistochemistry. Cell-type specific expression was examined in isolated astrocytic and microglial cell cultures. Cytokine and chemokine production was measured in IL-17A treated cultures to evaluate the functional status of IL-17RA.ResultsHere we report increased IL-17RA expression in the CNS of mice with EAE, and constitutive expression of functional IL-17RA in mouse CNS tissue. Specifically, astrocytes and microglia express IL-17RA in vitro, and IL-17A treatment induces biological responses in these cells, including significant upregulation of MCP-1, MCP-5, MIP-2 and KC chemokine secretion. Exogenous IL-17A does not significantly alter the expression of IL-17RA in glial cells, suggesting that upregulation of chemokines by glial cells is due to IL-17A signaling through constitutively expressed IL-17RA.ConclusionIL-17RA expression is significantly increased in the CNS of mice with EAE compared to healthy mice, suggesting that IL-17RA signaling in glial cells can play an important role in autoimmune inflammation of the CNS and may be a potential pathway to target for therapeutic interventions.

Leuprolide Acetate Inhibits Spinal Cord Inflammatory Response in Experimental Autoimmune Encephalomyelitis by Suppressing NF-κB Activation

“…Furthermore, it was demonstrated that IL-17A produced by Th17 cells can promote the disruption of the blood-brain barrier (BBB) in vitro [44]. Sarma et al [45] found that IL-17RA expression is significantly increased in the CNS of mice with EAE, including significant upregulation of chemokine secretion. These and other studies have suggested that IL-17A is required for induction of EAE, so the downregulation of its expression induced by LA treatment might be related to the improvement of clinical signs.…”

The role of IL-17 in CNS diseases

“…Both human [17] and mouse [14] astrocytes express the IL-17RA, thereby allowing for IL-17A ligation and consequently the production of cytokines and chemokines, including IL-6, TNFα, CCL2 (MCP-1), CCL3 (MIP-1α), CCL20 (MIP-3α), CXCL1 (GROα), CXCL2 (MIP-2), CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (IP-9) (Fig. 2).…”

“…Taking this into account, it is somewhat surprising how little is known about the microglial reaction to IL-17 stimulation in the context of MS/ EAE. These cells express low levels of the IL-17RA in steady state, which is up-regulated during EAE [14,38]. Upon in vitro stimulation with IL-17, microglia up-regulate the production of inflammatory mediators, including IL-6 and CXCL2, as well as neurotrophic factors, including NGF, BDNF and GDNF (Fig.…”

Polarization of macrophages and microglia in inflammatory demyelination

“…Chemokines released from both M1 (CCL8, CCL15, CCL19, CCL20, CXCL9, CXCL10, CXCL11 and CXCL13) and M2 (CCL13, CCL14, CCL17, CCL18, CCL22, CCL23, CCL24 and CCL26) cells contribute to leukocyte migration and infiltration into the CNS [8,[84][85][86] . it was reported that CXCR3, the receptor of CXCL9, CXCL10 and CXCL11, promotes the infiltration of T-reg cells into the CNS and ameliorates the severity of EAE [87] .…”