The RNA-binding protein tristetraprolin regulates RALDH2 expression by intestinal dendritic cells and controls local Treg homeostasis

Abstract

AU-rich element (ARE)-mediated mRNA decay represents a key mechanism to avoid excessive production of inflammatory cytokines. Tristetraprolin (TTP, encoded by Zfp36) is a major ARE-binding protein, since Zfp36 −/− mice develop a complex multiorgan inflammatory syndrome that shares many features with spondyloarthritis. The role of TTP in intestinal homeostasis is not known. Herein, we show that Zfp36 −/− mice do not develop any histological signs of gut pathology. However, they display a clear increase in intestinal inflammatory markers and discrete alterations in microbiota composition. Importantly, oral antibiotic treatment reduced both local and systemic joint and skin inflammation. We further show that absence of overt intestinal pathology is associated with local expansion of regulatory T cells. We demonstrate that this is related to increased vitamin A metabolism by gut dendritic cells, and identify RALDH2 as a direct target of TTP. In conclusion, these data bring insights into the interplay between microbiota-dependent gut and systemic inflammation during immune-mediated disorders, such as spondyloarthritis.

Conceptual Advances in Control of Inflammation by the RNA-Binding Protein Tristetraprolin

“…The absence of mucosal inflammation in TTP-deficient mice suggests that TTP has more complex roles in these tissues. Such functional complexity is supported by findings showing that the lack of intestinal pathology in TTP knockout mice is associated with a local expansion of regulatory T cells (57). Moreover, Villin-Credriven TTP deletion in intestinal epithelial cells increases the resistance against dextran sulfate-induced colitis suggesting, that the lack of TTP might enhance the robustness of the intestinal barrier (58).…”