title: Alterations to chromatin in intestinal macrophages link IL-10 deficiency to inappropriate inflammatory responses.
abstract: Intestinal macrophages (IMs) are uniquely programmed to tolerate exposure to bacteria without mounting potent inflammatory responses. The cytokine IL-10 maintains the macrophage anti-inflammatory response such that loss of IL-10 results in chronic intestinal inflammation. To investigate how IL-10-deficiency alters IM programming and bacterial tolerance, we studied changes in chromatin accessibility in response to bacteria in macrophages from two distinct niches, the intestine and bone-marrow, from both wild-type and IL-10-deficient (Il10(-/-) ) mice. We identified chromatin accessibility changes associated with bacterial exposure and IL-10 deficiency in both bone marrow derived macrophages and IMs. Surprisingly, Il10(-/-) IMs adopted chromatin and gene expression patterns characteristic of an inflammatory response, even in the absence of bacteria. Further, when recombinant IL-10 was added to Il10(-/-) cells, it could not revert the chromatin landscape to a normal state. Our results demonstrate that IL-10 deficiency results in stable chromatin alterations in macrophages, even in the absence of bacteria. This supports a model in which IL-10-deficiency leads to chromatin alterations that contribute to a loss of IM tolerance to bacteria, which is a primary initiating event in chronic intestinal inflammation.
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Simon
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Davis
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Saangyoung E
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Schaner
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Gipson
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.|Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Weiser
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.|Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.|Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.affiliation: Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.|Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Herfarth
authors.affiliation: Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Rahbar
authors.affiliation: Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Sadiq
authors.affiliation: Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Koruda
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Dermot P
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Department of Human Genetics, University of Chicago, IL, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lieb
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.|Department of Biology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Terrence S
authors.initials: TS
authors.lastname: Furey
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.|Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.|Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics*; D007422:Intestines / Q000276:immunology / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D002843:Chromatin; D016207:Cytokines; C508609:IL10 protein, human; C556062:IL10 protein, mouse; D016753:Interleukin-10
keywords: Chromatin accessibility; Chronic inflammation; IL-10; Inflammatory bowel disease; Macrophages