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World J Gastroenterol. Jul 14, 2022; 28(26): 3063-3070
Published online Jul 14, 2022. doi: 10.3748/wjg.v28.i26.3063
Alterations of autophagic and innate immune responses by the Crohn’s disease-associated ATG16L1 mutation
Natsuki Okai, Tomohiro Watanabe, Kosuke Minaga, Ken Kamata, Hajime Honjo, Masatoshi Kudo
Natsuki Okai, Tomohiro Watanabe, Kosuke Minaga, Ken Kamata, Hajime Honjo, Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan
Author contributions: Okai N and Watanabe T drafted the manuscript; Watanabe T, Minaga K, Kamata K, Honjo H, and Kudo M revised the manuscript; OKai N, Watanabe T, Minaga K, Kamata K, Honjo H and Kudo M have read and approved the final manuscript.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Tomohiro Watanabe, MD, PhD, Associate Professor, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Osaka, Japan. tomohiro@med.kindai.ac.jp
Received: January 10, 2022
Peer-review started: January 10, 2022
First decision: April 16, 2022
Revised: April 21, 2022
Accepted: June 16, 2022
Article in press: June 16, 2022
Published online: July 14, 2022
Abstract

Crohn’s disease (CD) is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines. These pro-inflammatory cytokines are produced by macrophages and dendritic cells (DCs) upon sensing the intestinal microbiota by the pattern recognition receptors (PRRs). Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation, as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development. Autophagy is an intracellular degradation process, during which cytoplasmic nutrients and intracellular pathogens are digested. Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs, it is likely that dysfunction of the autophagic machinery is involved in the development of CD. Indeed, the loss-of-function mutation T300A in the autophagy related 16 like 1 (ATG16L1) protein, a critical regulator of autophagy, increases susceptibility to CD. Recent studies have provided evidence that ATG16L1 is involved not only in autophagy, but also in PRR-mediated signaling pathways. ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs. Here, we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.

Keywords: ATG16L1, Crohn’s disease, Autophagy, Innate immunity, Cytokine, Pattern recognition receptors

Core Tip: The loss-of-function mutation T300A in autophagy related 16 like 1 (ATG16L1) increases the risk of Crohn’s disease (CD). ATG16L1 is a multifunctional protein involved in autophagy and innate immunity. The CD-associated ATG16L1 mutation T300A leads to overgrowth of intestinal microbiota and enhanced pro-inflammatory cytokine responses, which disrupt intestinal immune homeostasis. In this minireview article, we have summarized the immunopathogenesis of CD in the presence of ATG16L1 mutation.