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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)514-525.e6
JournalImmunity
Volume54
Issue number3
DOIs
Publication statusPublished - 2021 Mar 9
Externally publishedYes

Keywords

  • IL23r
  • Maf
  • Th17
  • helper T cells
  • intestine
  • miR-221
  • miR-222
  • miRNA
  • mucosal barrier damage
  • negative feedback

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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