The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells

Abstract

In both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), the C-C chemokine receptor 6 (CCR6) is critical for pathogenic T helper 17 (Th17) cell migration to the central nervous system (CNS). Whereas many cytokines and their receptors are potently regulated via post-transcriptional mechanisms in response to various stimuli, how CCR6 expression is post-transcriptionally regulated in Th17 cells is unknown. Here, using RNA-binding protein HuR conditional knock-out (KO) and wild-type (WT) mice, we present evidence that HuR post-transcriptionally regulates CCR6 expression by binding to and stabilizing mRNA and by promoting CCR6 translation. We also found that HuR down-regulates several microRNA expressions, which could target the 3'-UTR of Ccr6 mRNA for decay. Accordingly, knock-out of HuR reduced CCR6 expression on Th17 cells and impaired their migration to CNS compared with the response of WT Th17 cells and thereby ameliorated EAE. Together, these findings highlight how HuR contributes to Th17 cell-mediated autoimmune neuroinflammation and support the notion that targeting HuR might be a potential therapeutic intervention for managing autoimmune disorders of the CNS.

The increased protection and pathology in Mycobacterium tuberculosis-infected IL-27R-alpha-deficient mice is supported by IL-17A and is associated with the IL-17A-induced expansion of multifunctional T cells

“…During experimental TB, IL-27R regulates gene expression of Ccl20 and the accumulation of CCR6-expressing CD4 T cells C-C chemokine receptor 6 (CCR6) is expressed by Th17 cells 54,55 and is critical for the migration of murine Th17 cells into inflamed tissues. 56,57 Therefore, we were wondering whether during experimental TB the frequency of antigen-specific CCR6-expressing CD4 T cells is modulated in the absence of IL-27R-mediated signaling ( Fig. 7a).…”

RNA binding proteins in the control of autoimmune diseases

“…Moreover, the adoptive transfer of HuR-deficient Th17 cells leads to the delayed onset and amelioration of disease severity of EAE compared to controls [84]. In addition, HuR up-regulates the expression of CCR6 by promoting its translation and/or mRNA stabilization, enhancing the infiltration of Th17 cells into the CNS [85]. In another line of study, HuR in B cells has been shown to be important for the germinal center reaction and the class-switched antibody production via the regulation of splicing [86].…”

Post‐transcriptional control of immune responses and its potential application

“…Mechanistically, HuR stabilises Il17 mRNA and promotes T‐cell proliferation under the conditions of EAE. In addition, HuR upregulates the expression of the chemokine receptor CCR6 by promoting its translation and/or mRNA stabilisation, further enhancing the infiltration of Th17 cells into the CNS …”

“…In addition, HuR upregulates the expression of the chemokine receptor CCR6 by promoting its translation and/or mRNA stabilisation, further enhancing the infiltration of Th17 cells into the CNS. 67 Inflammation in the central nervous system is also linked with iron metabolism. Members of the poly(rC) binding protein (PCBP) family are multifunctional proteins that serve as an iron chaperones and RNA binding proteins.…”