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

Authors

• Seth D. Merkley, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Samuel M. Goodfellow, Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Yan Guo, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Zoe E R Wilton, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Janie R. Byrum, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Kurt C. Schwalm, Department of Pediatrics, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Darrell L. Dinwiddie, Department of Pediatrics, University of New Mexico Health Sciences, Albuquerque, NM, USA; Clinical and Translational Science Center, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Rama R. Gullapalli, Department of Pathology, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences, Albuquerque, NM, USA; Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Anthony Jimenez Hernandez, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Steven B. Bradfute, Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA
• Julie G. In, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
• Eliseo F. Castillo, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM, USA; Clinical and Translational Science Center, University of New Mexico Health Sciences, Albuquerque, NM, USA; Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences, Albuquerque, NM, USA

Document Type

Article

Publication Date

2-23-2022

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 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.

Publication Title

J Crohns Colitis

ISSN

1876-4479

Volume

16

Issue

2

First Page

259

Last Page

274

DOI

10.1093/ecco-jcc/jjab144

Recommended Citation

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.

Comments

• PMCID: PMC8864635 (available on 2022-08-10)