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

• Published in: bioRxiv
• Main Authors: Merkley, Seth D, Goodfellow, Samuel M, Guo, Yan, Zoe Er Wilton, Byrum, Janie R, Schwalm, Kurt C, Dinwiddie, Darrell L, Gullapalli, Rama R, Deretic, Vojo, Anthony Jimenez Hernandez, Bradfute, Steven B, Julie G In, Castillo, Eliseo F
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.12.2020
• Subjects: Acidity; Autophagy; Colitis; Dysbacteriosis; Endosomes; Homeostasis; Inflammation; Inflammatory bowel disease; Interleukin 12; Intestinal microflora; Intestine; Microbiota; Myeloid cells; Phagocytosis; γ-Interferon
• DOI: 10.1101/2020.12.07.414227

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 prior to colitis and exhibited severe intestinal inflammation upon colitis induction that was characterized by increased IFNγ production. This increase in IFNγ 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 Atg5ΔMye mice. 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.