Dysregulation of CD177+ neutrophils on intraepithelial lymphocytes exacerbates gut inflammation via decreasing microbiota-derived DMF

Neutrophils synergize with intestinal resident intraepithelial lymphocytes (IELs) to serve as the first-line defense and maintain intestinal homeostasis. However, the underlying mechanisms whereby neutrophils regulate IELs to inhibit intestinal inflammation are still not completely understood. Here, we found that depletion of neutrophils (especially CD177(+) subset) caused expansion of colitogenic TCR gamma delta(+)CD8 alpha alpha(+) IELs, increased intestinal inflammation, and dysbiosis after dextran sulfate sodium exposure or Citrobacter rodentium infection in mice. scRNA-seq analysis revealed a pyroptosis-related gene signature and hyperresponsiveness to microbiota in TCR gamma delta(+)CD8 alpha alpha(+) IELs from colitic Cd177 (-/-) mice. Microbiota-derived fumarate and its derivative dimethyl fumarate (DMF), as well as fumarate-producing microbiotas, decreased in the feces of colitic Cd177 (-/-) mice. Elimination of dysbiosis by antibiotics treatment or co-housing procedure and DMF supplementation restrained TCR gamma delta(+)CD8 alpha alpha(+) IEL activation. Consistently, DMF significantly alleviated intestinal mucosal inflammation in mice through restricting gasdermin D (GSDMD)-induced pyroptosis of TCR gamma delta(+)CD8 alpha alpha(+) IELs. Therefore, our data reveal that neutrophils inhibit intestinal inflammation by promoting microbiota-derived DMF to regulate TCR gamma delta(+)CD8 alpha alpha(+) IEL activation in a GSDMD-mediated pyroptosis-dependent manner, and that DMF may serve as a therapeutic target for the management of intestinal inflammation.

Automated summary

Neutrophils synergize with intraepithelial lymphocytes (IELs) to maintain intestinal homeostasis, but the mechanisms underlying their regulation of IELs and intestinal inflammation are not completely understood. Depletion of neutrophils, particularly the CD177(+) subset, led to expansion of colitogenic TCR gamma delta(+)CD8 alpha alpha(+) IELs, increased intestinal inflammation, and dysbiosis in mice. The dysbiosis was associated with decreased levels of microbiota-derived fumarate and its derivative dimethyl fumarate (DMF), which play a role in regulating TCR gamma delta(+)CD8 alpha alpha(+) IEL activation. DMF supplementation alleviated intestinal mucosal inflammation and restricted TCR gamma delta(+)CD8 alpha alpha(+) IEL pyroptosis, suggesting that DMF may be a therapeutic target for intestinal inflammation.