Inhibition of Piezo1 Ameliorates Intestinal Inflammation and Limits the Activation of Group 3 Innate Lymphoid Cells in Experimental Colitis

J Innate Immun. 2023;15(1):709-723. doi: 10.1159/000533525. Epub 2023 Sep 19.

Abstract

Piezo1, the mechanosensory ion channel, has attracted increasing attention for its essential roles in various inflammatory responses and immune-related diseases. Although most of the key immune cells in inflammatory bowel disease (IBD) have been reported to be regulated by Piezo1, the specific role of Piezo1 in colitis has yet to be intensively studied. The present study investigated the impact of pharmacological inhibition of Piezo1 on dextran sulfate sodium (DSS)-induced colitis and explored the role of Piezo1 in intestinal immune cells in the context of colitis. We observed upregulated expression of Piezo1 in the colon tissue of mice with DSS-induced colitis. Pharmacological inhibition of Piezo1 by GsMTx4 diminished the severity of colitis. Piezo1 inhibition downregulated the expression of pro-inflammatory mediators Il1b, Il6, and Ptgs2 in colonic tissue and suppressed the production of IL-6 from macrophages and dendritic cells without altering the balance of T helper (Th) cells. In particular, Piezo1 did not affect cell viability but regulated cell proliferation and production of IL-17A in group 3 innate lymphoid cells (ILC3s), which is dependent on the PI3K-Akt-mTOR signaling pathway. Our findings uncover Piezo1 as an effective regulator of gut inflammation. Targeting Piezo1 could be a promising strategy to modulate intestinal immunity in IBD.

Keywords: Group 3 innate lymphoid cells; GsMTx4; Inflammatory bowel disease; Piezo1.

MeSH terms

  • Animals
  • Colitis* / chemically induced
  • Colitis* / metabolism
  • Colon / metabolism
  • Disease Models, Animal
  • Immunity, Innate*
  • Inflammation / metabolism
  • Ion Channels* / antagonists & inhibitors
  • Ion Channels* / genetics
  • Ion Channels* / metabolism
  • Lymphocytes* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / metabolism

Substances

  • Ion Channels
  • Phosphatidylinositol 3-Kinases
  • Piezo1 protein, mouse

Grants and funding

This work was supported by the National Natural Science Foundation of China [Grant No. 82070551, 82270570]; the Taishan Scholars Program of Shandong Province; and the Natural Science Youth Foundation of Shandong Province [Grant No. ZR2020QH030]. The funding sources had no role in the study design; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit it for publication.