Non-autophagy Role of Atg5 and NBR1 in Unconventional Secretion of IL-12 Prevents Gut Dysbiosis and Inflammation.

Journal of Crohn's & colitis 2022 Feb 23

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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. © The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Citation

Seth D Merkley, Samuel M Goodfellow, Yan Guo, Zoe E R Wilton, Janie R Byrum, Kurt C Schwalm, Darrell L Dinwiddie, Rama R Gullapalli, Vojo Deretic, Anthony Jimenez Hernandez, Steven B Bradfute, Julie G In, Eliseo F Castillo. Non-autophagy Role of Atg5 and NBR1 in Unconventional Secretion of IL-12 Prevents Gut Dysbiosis and Inflammation. Journal of Crohn's & colitis. 2022 Feb 23;16(2):259-274