4.8 Article

Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells

Journal

IMMUNITY
Volume 54, Issue 6, Pages 1137-+

Publisher

CELL PRESS
DOI: 10.1016/j.immuni.2021.05.008

Keywords

-

Categories

Funding

  1. Lupus Research Alliance
  2. NIH [AI128358]
  3. EMBO long term postdoctoral fellowship [ALTF 534-2017]
  4. Crohn's and Colitis Foundation [708946]
  5. GSK postdoctoral fellowship
  6. Cancer Research Institute

Ask authors/readers for more resources

Alterations in the cGAS-STING DNA-sensing pathway can affect intestinal homeostasis and lead to inflammation. Increased STING expression is a feature of intestinal inflammation in both mice with colitis and humans with inflammatory bowel disease. STING accumulation in intestinal myeloid cells can be triggered by dysbiosis and bacterial products, leading to a positive feedback loop that drives intestinal inflammation.
Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease. Mice bearing an allele rendering STING constitutively active exhibited spontaneous colitis and dysbiosis, as well as progressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experiments revealed STING accumulation in intestinal macrophages and monocytes as the initial driver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulation in these cells and alleviated intestinal inflammation. STING accumulation occurred at the protein rather than transcript level, suggesting post-translational stabilization. We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitination could be elicited by bacterial products, including cyclic di-GMP. Our findings suggest a positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinal myeloid cells, driving intestinal inflammation.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available