MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23

• DOI: 10.1016/j.immuni.2021.02.015
• Publication Date: 2021-03-02T16:58:39Z
• Authors: Yohei Mikami; Rachael L. Philips; Giuseppe Sciumè; Franziska Petermann; Françoise Meylan; Hiroyuki Nagashima; Chen Yao; Fred P. Davis; Stephen R. Brooks; Hong-Wei Sun; Hayato Takahashi; Amanda C. Poholek; Han-Yu Shih; Behdad Afzali; Stefan A. Muljo; Markus Hafner; Yuka Kanno; John J. O’Shea
• Keywords: Feedback, Physiological; Inflammation; Mice, Knockout; 0301 basic medicine; 0303 health sciences; Receptors, Interleukin; Interleukin-23; helper T cells; IL23r; intestine; Maf; miR-221; miR-222; miRNA; mucosal barrier damage; negative feedback; Th17; Mice, Inbred C57BL; Mice; MicroRNAs; 03 medical and health sciences; Transforming Growth Factor beta; Proto-Oncogene Proteins c-maf; Animals; Th17 Cells; Intestinal Mucosa; Signal Transduction

MicroRNAs are important regulators of immune responses. Here, we show miR-221 and miR-222 modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-β. Molecular targets of miR-221 and miR-222 included Maf and Il23r, and loss of miR-221 and miR-222 expression shifted the transcriptomic spectrum of intestinal Th17 cells to a proinflammatory signature. Although the loss of miR-221 and miR-222 was tolerated for maintaining intestinal Th17 cell homeostasis in healthy mice, Th17 cells lacking miR-221 and miR-222 expanded more efficiently in response to IL-23. Both global and T cell-specific deletion of miR-221 and miR-222 rendered mice prone to mucosal barrier damage. Collectively, these findings demonstrate that miR-221 and miR-222 are an integral part of intestinal Th17 cell response that are induced after IL-23 stimulation to constrain the magnitude of proinflammatory response.