RNA-binding protein HuR promotes Th17 cell differentiation and targeting HuR reduces autoimmune neuroinflammation

Abstract

Abstract Dysregulated Th17 cell differentiation is associated with autoimmune diseases such as multiple sclerosis, which has no curative treatment. Understanding the molecular mechanisms of regulating Th17 cell differentiation will help in identifying a novel therapeutic target for treating Th17 cell-mediated diseases. Here, we investigated the cell-intrinsic processes by which RNA-binding protein HuR orchestrates Th17 cell fate decisions by post-transcriptionally regulating transcription factor Irf4 and Runx1 and receptor Il12rb1 expression, in turn promoting Th17 cell and Th1-like Th17 cell differentiation. Knockout of HuR impaired the transcriptome of Th17 cells characterized by reduced levels of RORγt, IRF4, RUNX1, and T-bet, thereby reducing the number of pathogenic IL-17+IFN-γ+CD4+ T cells during experimental autoimmune encephalomyelitis (EAE). In keeping with the fact that HuR increased the expression of adhesion molecule VLA-4 on Th17 cells, knockout of HuR impaired Th17 cell migration to the central nervous system and abolished the disease. Accordingly, targeting HuR by its inhibitor, DHTS, suppressed Th17 cell differentiation and reduced EAE severity. In sum, we uncovered the molecular mechanism underlying HuR’s regulation of Th17 cell differentiation and functions, underscoring the therapeutic value of HuR as a novel treatment for autoimmune neuroinflammation. (Supported by NIH R01 AI119135)