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- Title
Non-autophagy Role of Atg5 and NBR1 in Unconventional Secretion of IL-12 Prevents Gut Dysbiosis and Inflammation.
- Authors
Merkley, Seth D; Goodfellow, Samuel M; Guo, Yan; Wilton, Zoe E R; Byrum, Janie R; Schwalm, Kurt C; Dinwiddie, Darrell L; Gullapalli, Rama R; Deretic, Vojo; Hernandez, Anthony Jimenez; Bradfute, Steven B; In, Julie G; Castillo, Eliseo F
- Abstract
Intestinal myeloid cells play a critical role in balancing intestinal homeostasis and inflammation. Here, we report that expression of the autophagy-related 5 [Atg5] protein in myeloid cells prevents dysbiosis and excessive intestinal inflammation by limiting IL-12 production. Mice with a selective genetic deletion of Atg5 in myeloid cells [Atg5ΔMye] showed signs of dysbiosis preceding colitis, and exhibited severe intestinal inflammation upon colitis induction that was characterised by increased IFNγ production. The exacerbated colitis was linked to excess IL-12 secretion from Atg5 -deficient myeloid cells and gut dysbiosis. Restoration of the intestinal microbiota or genetic deletion of IL-12 in Atg5ΔMye mice attenuated the intestinal inflammation in Atg5ΔMye mice. Additionally, Atg5 functions to limit IL-12 secretion through modulation of late endosome [LE] acidity. Last, the autophagy cargo receptor NBR1, which accumulates in Atg5-deficient cells, played a role by delivering IL-12 to LE. In summary, Atg5 expression in intestinal myeloid cells acts as an anti-inflammatory brake to regulate IL-12, thus preventing dysbiosis and uncontrolled IFNγ-driven intestinal inflammation.
- Publication
Journal of Crohn's & Colitis, 2022, Vol 16, Issue 2, p259
- ISSN
1873-9946
- Publication type
Article
- DOI
10.1093/ecco-jcc/jjab144