title: Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis.
abstract: Intact ATG16L1 plays an essential role in Paneth cell function and intestinal homeostasis. However, the functional consequences of ATG16L1 deficiency in myeloid cells, particularly macrophages, are not fully characterized. We generated mice with Atg16l1 deficiency in myeloid and dendritic cells and showed that mice with myeloid Atg16l1 deficiency had exacerbated colitis in two acute and one chronic model of colitis with increased proinflammatory to anti-inflammatory macrophage ratios, production of proinflammatory cytokines, and numbers of IgA-coated intestinal microbes. Mechanistic analyses using primary murine macrophages showed that Atg16l1 deficiency led to increased reactive oxygen species production, impaired mitophagy, reduced microbial killing, impaired processing of MHC class II Ags, and altered intracellular trafficking to the lysosomal compartments. Increased production of reactive oxygen species and reduced microbial killing may be general features of the myeloid compartment, as they were also observed in Atg16l1-deficient primary murine neutrophils. A missense polymorphism (Thr300Ala) in the essential autophagy geneATG16L1is associated with Crohn disease (CD). Previous studies showed that this polymorphism leads to enhanced cleavage of ATG16L1 T300A protein and thus reduced autophagy. Similar findings were shown in primary human macrophages from controls and a population of CD patients carrying theAtg16l1 T300Arisk variant and who were controlled forNOD2CD-associated variants. This study revealed that ATG16L1 deficiency led to alterations in macrophage function that contribute to the severity of CD.
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.|Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China; and.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China; and.
authors.forename: Libo
authors.initials: L
authors.lastname: Zheng
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Ariel M
authors.identifier: 0000-0002-8400-8821
authors.initials: AM
authors.lastname: Hamill
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Ryan
authors.initials: R
authors.lastname: Ichikawa
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Kanazawa
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Justin
authors.initials: J
authors.lastname: Luu
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Electron Microscopy Core Facility, Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Marianne
authors.initials: M
authors.lastname: Cilluffo
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: David M
authors.identifier: 0000-0002-2989-658X
authors.initials: DM
authors.lastname: Underhill
authors.affiliation: Department of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China; and david.shih@csmc.edu xiaolanzh@126.com.
authors.forename: Xiaolan
authors.identifier: 0000-0002-7047-3634
authors.initials: X
authors.lastname: Zhang
authors.affiliation: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; david.shih@csmc.edu xiaolanzh@126.com.
authors.forename: David Q
authors.identifier: 0000-0003-1335-7044
authors.initials: DQ
authors.lastname: Shih
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology; D000071183:Autophagy-Related Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology*; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006706:Homeostasis; D054884:Host-Pathogen Interactions; D006801:Humans; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D019879:Paneth Cells / Q000276:immunology* / Q000382:microbiology; D011110:Polymorphism, Genetic; D012306:Risk; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein