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Myeloid ATG16L1 Facilitates Host–Bacteria Interactions in Maintaining Intestinal Homeostasis

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Myeloid ATG16L1 Facilitates Host–Bacteria Interactions in Maintaining Intestinal Homeostasis Myeloid ATG16L1 Facilitates Host−Bacteria Interactions in Maintaining Intestinal Homeostasis This information is current as Hong Zhang, Libo Zheng, Dermot P. B. McGovern, Ariel of October 2, 2021. M. Hamill, Ryan Ichikawa, Yoshitake Kanazawa, Justin Luu, Kotaro Kumagai, Marianne Cilluffo, Masayuki Fukata, Stephan R. Targan, David M. Underhill, Xiaolan Zhang and David Q. Shih J Immunol published online 27 January 2017 http://www.jimmunol.org/content/early/2017/01/27/jimmun Downloaded from ol.1601293 Supplementary http://www.jimmunol.org/content/suppl/2017/01/27/jimmunol.160129 http://www.jimmunol.org/ Material 3.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 27, 2017, doi:10.4049/jimmunol.1601293 The Journal of Immunology Myeloid ATG16L1 Facilitates Host–Bacteria Interactions in Maintaining Intestinal Homeostasis Hong Zhang,*,† Libo Zheng,† Dermot P. B. McGovern,* Ariel M. Hamill,* Ryan Ichikawa,* Yoshitake Kanazawa,* Justin Luu,* Kotaro Kumagai,* Marianne Cilluffo,‡ Masayuki Fukata,* Stephan R. Targan,* David M. Underhill,* Xiaolan Zhang,† and David Q. Shih* 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 macro- Downloaded from phages showed that Atg16l1 deficiency led to increased reactive oxygen species production, impaired mitophagy, reduced micro- bial 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 compart- ment, as they were also observed in Atg16l1-deficient primary murine neutrophils. A missense polymorphism (Thr300Ala) in the essential autophagy gene ATG16L1 is 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 http://www.jimmunol.org/ macrophages from controls and a population of CD patients carrying the Atg16l1 T300A risk variant and who were controlled for NOD2 CD-associated variants. This study revealed that ATG16L1 deficiency led to alterations in macrophage function that contribute to the severity of CD. The Journal of Immunology, 2017, 198: 000–000. nflammatory bowel diseases (IBD) are chronic debilitating The IBD-associated single nucleotide polymorphism (SNP) inflammatory conditions, which are classically differentiated ATG16L1 T300A is a loss-of-function SNP that leads to increased I into Crohn disease (CD) and ulcerative colitis. To date, .200 caspase-mediated cleavage of ATG16L1 protein (10–12). The susceptibility loci have been identified (1–3). One of the genetic functional consequences of ATG16L1 T300A were assessed in by guest on October 2, 2021 variants at position 300 in the autophagy gene ATG16L1 resulted mice with knock-in of the human ATG16L1 T300A gene (10). The in a threonine to alanine substitution (T300A) in the C-terminal mice in this study developed defective and abnormal appearing domain (2, 4). Macroautophagy (herein referred to as autophagy) Paneth cells and goblet cells, reduced bacteria clearance, in- described a bulk degradation system where cytosolic constituents creased IL-1b production, and worsened cecal inflammation with were engulfed in a double-membrane vesicle and targeted for Salmonella infection compared with wild-type (WT) mice. An- degradation by lysosomal fusion (reviewed in Ref. 5). Selective other group independently showed reduced bacteria clearance and autophagy, such as mitophagy to remove damaged mitochondria, increased expression of IL-1b in primary human ATG16L1 T300A also removed cellular danger signals and is thought to act as a macrophages and mouse ATG16L1 T316A knock-in (correspond- break for the NLRP3 inflammasome (6–9). ing to human ATG16L1 T300A) macrophages (11). *F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, mitochondria luminol studies; J.L., K.K., and M.F. performed the neutrophil assays; Cedars-Sinai Medical Center, Los Angeles, CA 90048; †Department of Gastroenter- Y.K. assisted in animal sacrifice and flow cytometry analysis; M.C. was involved in ology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, design and analysis of TEM studies; M.F. was involved in design and analysis of China; and ‡Electron Microscopy Core Facility, Brain Research Institute, University Salmonella infection model and Salmonella uptake studies; D.Q.S. wrote the paper; of California Los Angeles, Los Angeles, CA 90095 and all authors discussed the results and commented on the manuscript. ORCIDs: 0000-0002-8400-8821 (A.M.H.); 0000-0002-2989-658X (D.M.U.); 0000- Address correspondence and reprint requests to Dr. David Q. Shih or Dr. Xiaolan 0002-7047-3634 (X.Z.); 0000-0003-1335-7044 (D.Q.S.). Zhang, Cedars-Sinai Inflammatory Bowel and Immunobiology Research Institute, 8700 Beverly Boulevard, Suite 4066, Los Angeles, CA 90048 (D.Q.S.) or Depart- Received for publication July 26, 2016. Accepted for publication December 28, 2016. ment of Gastroenterology, Second Hospital of Hebei Medical University, 215 West This work was supported by U.S. Public Health Service Grant DK056328 and Na- Heping Road, Shijiazhuang, Hebei 050000, China (X.Z.). E-mail addresses: david. tional Institutes of Health Grant P01 DK046763 (to S.R.T.), National Institutes of [email protected] (D.Q.S.) or [email protected] (X.Z.) Health K08 Career Development Award DK093578 (to D.Q.S.), Crohn’s and Colitis The online version of this article contains supplemental material. Foundation of America Career Development Award 3467 (to D.Q.S.), National Cen- ter for Advancing Translational Sciences Grant UL1TR000124 (to D.Q.S.), and by Abbreviations used in this article: BMM, bone marrow–derived macrophage; CD, funding from the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Crohn disease; DC, dendritic cell; DSS, dextran sodium sulfate; IBD, inflammatory Research Institute. The MIRIAD Biobank is currently supported by the F. Widjaja bowel disease; LPMC, lamina propria mononuclear cell; MFI, mean fluorescence Foundation Inflammatory Bowel and Immunobiology Research Institute, National intensity; MHC-II, MHC class II; MLN, mesenteric lymph node; MOI, multiplicity Institutes of Health Grant P01 DK046763, European Union Grant 305479, National of infection; PBM, peripheral blood monocyte-derived macrophage; ROS, reactive Institute of Diabetes and Digestive and Kidney Diseases Grants DK062413 and U54 oxygen species; SNP, single nucleotide polymorphism; TEM, transmission electron DK102557, and by the Leona M. and Harry B. Helmsley Charitable Trust. microscopy; WT, wild-type. H.Z., L.Z., D.P.B.M., S.R.T., D.M.U., X.Z., and D.Q.S. designed the research studies Ó and analyzed the data; H.Z. and L.Z. performed most of the experiments; A.M.H. Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 performed mitochondrial studies; R.I. performed Salmonella clearance and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601293 2 MYELOID ATG16L1 MAINTAINS INTESTINAL HOMEOSTASIS The cell-specific role of autophagy was reported using condi- (LysM-cre, The Jackson Laboratory stock 004781), and CD11c (CD11c- tional Atg16l1 knockout mice, in which Atg16l1 was deleted cre, The Jackson Laboratory stock 007567). For Ag presentation assay, specifically in intestinal epithelial cells or CD11c+ dendritic cells OTII/RAGII mice (Taconic model 1896) specific for OVA323–339 were used. All mice were in the C57BL/6J genetic background and were main- (DC) (13). Compared to WT, mice with epithelial Atg16l1 defi- tained under specific pathogen-free conditions in the Animal Facility at ciency exhibited Paneth cell abnormalities and were more sus- Cedars-Sinai Medical Center. This study was carried out in strict accordance ceptible to Salmonella typhimurium infection, whereas the phenotype with the Guide for the Care and Use of Laboratory Animals of the National of Atg16l1 deficiency in CD11c+ DC was similar to control WT Institutes of Health. Animal studies were approved by the Cedars-Sinai Medical Center Animal Care and Use Committee (protocol
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