Non-autophagy role of Atg5 and NBR1 in unconventional secretion of IL-12 prevents gut dysbiosis and inflammation

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 (Atg5{Delta}Mye) showed signs of dysbiosis prior to colitis and exhibited severe intestinal inflammation upon colitis induction that was characterized by increased IFN{gamma} production. This increase in IFN{gamma} was due to excess IL-12 secretion from Atg5-deficient myeloid cells. Atg5 functions to limit IL-12 secretion through modulation of late endosome (LE) acidity. Additionally, the autophagy cargo receptor NBR1, which accumulates in Atg5-deficient cells, played a role by delivering IL-12 to LE. Restoration of the intestinal microbiota and alleviation of intestinal inflammation was achieved by genetic deletion of IL-12 in Atg5{Delta}Mye mice. In summary, Atg5 expression in intestinal myeloid cells acts as an anti-inflammatory brake to regulate IL-12 thus preventing dysbiosis and uncontrolled IFN{gamma}-driven intestinal inflammation.