Roles of the RNA binding protein Arid5a in IL-17-mediated diseases

Abstract

Interleukin 17 is a proinflammatory cytokine required for host defense against extracellular microorganisms but also contributes to the pathogenesis of certain autoimmune diseases. Candida albicans is a commensal fungus that colonizes mucosal tissues. During immunosuppression, C. albicans can cause superficial infections, such as oropharyngeal candidiasis (OPC). Defects in IL-17 signaling increase susceptibility to OPC in both humans and mice. IL-17 receptor signaling involves RNA binding proteins (RBP) that regulate translation and stability of target mRNA transcripts. During OPC, IL-17 induces several RBPs including Arid5a. This RBP interacts with AU-rich elements located in the 3′ UTR of many inflammatory mRNAs. In T cells, loss of Arid5a reduces expression of IL-6 and STAT3 and leads to decreased frequency of Th17 cells. Consequently, Arid5a−/− mice are resistant to experimental autoimmune encephalomyelitis (EAE), an IL-17-driven model of multiple sclerosis. Although made by T cells, IL-17 signals on non-hematopoietic cell types. We reported an in vitro role for Arid5a in the downstream IL-17 receptor pathway. Specifically, Arid5a regulates stability and/or translation of several IL-17-dependent mRNAs including Il6. Accordingly, we postulated that Arid5a plays a critical role in protection against OPC by stabilizing and increasing expression of IL-17-responsive genes. To test this hypothesis, CRISPR/Cas9 was used to generate an Arid5a knockout mouse. We confirmed that Arid5a−/− mice are resistant to EAE. To ascertain the effects of Arid5a in OPC, we infected mice orally with C. albicans and assessed fungal loads and weight loss. Surprisingly, Arid5a−/− mice were resistant to OPC, in contrast to Il17ra−/− mice.