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.
J Crohns Colitis
Merkley SD, Goodfellow SM, Guo Y, Wilton ZER, Byrum JR, Schwalm KC, Dinwiddie DL, Gullapalli RR, Deretic V, Jimenez Hernandez A, Bradfute SB, In JG, Castillo EF. Non-autophagy Role of Atg5 and NBR1 in Unconventional Secretion of IL-12 Prevents Gut Dysbiosis and Inflammation. J Crohns Colitis. 2022 Feb 23;16(2):259-274. doi: 10.1093/ecco-jcc/jjab144. PMID: 34374750; PMCID: PMC8864635.