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 Ccr6 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.
Highlights
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)
Because CCR6 is crucial for the pathogenic Th17 cell migration in rheumatoid arthritis and EAE [10, 12, 29], we sought to investigate whether HuR regulates expression of CCR6 on Th17 cells
Differentiation of Th17 cells resulted in an average 2-fold increase in HuR protein expression levels in comparison with CD4ϩ T cells activated with anti-CD3 plus anti-CD28 and without Th17 cell polarization cytokines (Fig. 1, C and D). These findings suggest that the expression of CCR6 correlates with the level of HuR protein in Th17 cells, supporting our hypothesis that HuR positively promotes expression of CCR6 in Th17 cells
Summary
The initial trigger of inflammation is induced by CCR6-dependent autoreactive Th17 cell infiltration of the uninflamed CNS [12,13,14] In agreement with this notion, CCR6Ϫ/Ϫ mice are resistant to development of EAE [12]. HuR stabilizes many target mRNAs encoding proteins with roles in cell proliferation, survival, immune responses, and differentiation [27]. Knock-out of HuR decreases CCR6 expression on Th17 cells and impairs their migration in response to its ligand, CCL20, thereby ameliorating EAE. These results further support the notion that targeting HuR might be a novel therapeutic intervention for autoimmune encephalomyelitis [28]
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