title: The protection role of Atg16l1 in CD11c+dendritic cells in murine colitis.
abstract: The autophagy-related 16-like 1 gene (Atg16l1) is associated with inflammatory bowel disease (IBD) and has been shown to play an essential role in paneth cell function and intestinal homeostasis. However, the functional consequences of Atg16l1 deficiency in myeloid cells, particularly in dendritic cells (DCs), are not fully characterized. The aim of this study is to investigate the functional consequence of Atg16l1 in CD11c+DCs in murine colitis. We generated mice deficient in Atg16l1 in CD11c+DCs. Dextran Sulfate Sodium (DSS) and S. typhimurium infection induced colitis was used to assess the role of DCs specific Atg16l1 deficiency in vivo in murine colitis. Bone marrow derived dendritic cells (BMDC) were isolated and autophagy function was assessed with microtubule-associated protein 1 light chain 3β (Map1lc3b or LC3) by western blot. Uptake of Salmonella enteric serovar typhimurium (S. typhimurium) was assessed by flow cytometry and transmission electron microscopy (TEM). The production of reactive oxygen species (ROS) and intracellular S. typhimurium killing in BMDCs were assessed. We showed worsened colonic inflammation in Atg16l1 deficiency mice in DSS induced murine colitis with increased proinflammatory cytokines of IL-1β and TNF-α. Mechanistic studies performed in primary murine BMDCs showed that Atg16l1 deficiency increased ROS production, reduced microbial killing and impaired antigen processing for altered intracellular trafficking. Together, these results indicate impaired CD11c+DCs function with Atg16l1 deficiency contributes to the severity of murine colitis.
authors.affiliation: Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei, China; F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA90048, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Zheng
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA90048, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chen
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA90048, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA90048, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Ichikawa
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA90048, USA.
authors.forename: David Q
authors.initials: DQ
authors.lastname: Shih
authors.affiliation: Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei, China. Electronic address: xiaolanzh@126.com.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins; D039521:CD11c Antigen / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D003092:Colitis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004198:Disease Susceptibility; D007070:Immunoglobulin A / Q000276:immunology; D018836:Inflammation Mediators; D015212:Inflammatory Bowel Diseases; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010588:Phagosomes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D039521:CD11c Antigen; D002352:Carrier Proteins; D016207:Cytokines; D007070:Immunoglobulin A; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D016264:Dextran Sulfate
keywords: Atg16l1; Autophagy; Dendritic cells; IgA; Inflammatory bowel disease; ROS