Journal
IMMUNOBIOLOGY
Volume 222, Issue 7, Pages 831-841Publisher
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2017.03.002
Keywords
Inflammatory bowel disease; Autophagy; Atg16l1; Dendritic cells; ROS; IgA
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Funding
- Cedars-Sinai Inflammatory Bowel and Immunobiology Research Institute
- F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, NIH [P01 DK046763]
- European Union [305479]
- NIDDK [DK062413, U54 DK102557]
- Leona M and Harry B Helmsley Charitable Trust
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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 313 (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-1 beta and TNF-alpha. 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. (C) 2017 Elsevier GmbH. All rights reserved.
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