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 (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.

Polystyrene microplastics induce an immunometabolic active state in macrophages

“…Intestinal macrophages exhibit an anti-in ammatory phenotype under homeostatic conditions that allows them to function as highly phagocytic and bactericidal cells without initiating an in ammatory response (Bain and Schridde, 2018). A functional autophagic pathway in macrophages is critical for this anti-in ammatory phenotype (Lee et al, 2016;Merkley et al, 2020;Zhang et al, 2017). It is suggested that anti-in ammatory macrophages rely mainly on mitochondrial metabolism such as the oxidative phosphorylation (OXPHOS) and fatty acid oxidation for energy production (Diskin and Palsson-McDermott, 2018;Shanmugam et al, 2003).…”