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

Mucosal immunology 2021 Jan

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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.

Citation

Caroline La, Bérengère de Toeuf, Laure B Bindels, Laurye Van Maele, Assiya Assabban, Maxime Melchior, Justine Smout, Arnaud Köhler, Muriel Nguyen, Séverine Thomas, Romuald Soin, Nadège Delacourt, Hsüehlei Li, Wenqian Hu, Perry J Blackshear, Véronique Kruys, Cyril Gueydan, Guillaume Oldenhove, Stanislas Goriely. The RNA-binding protein tristetraprolin regulates RALDH2 expression by intestinal dendritic cells and controls local Treg homeostasis. Mucosal immunology. 2021 Jan;14(1):80-91