Alterations to chromatin in intestinal macrophages link IL‐10 deficiency to inappropriate inflammatory responses |
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| Authors: | Jeremy M. Simon James P. Davis Saangyoung E. Lee Matthew R. Schaner Gregory R. Gipson Matthew Weiser R. Balfour Sartor Hans H. Herfarth Reza Rahbar Timothy S. Sadiq Mark J. Koruda Dermot P. McGovern Jason D. Lieb Karen L. Mohlke Terrence S. Furey Shehzad Z. Sheikh |
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| Affiliation: | 1. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA;2. Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA;3. Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA;4. Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA;5. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA;6. Department of Surgery, University of North Carolina, Chapel Hill, NC, USA;7. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars‐Sinai Medical Center, Los Angeles, CA, USA;8. Department of Human Genetics, University of Chicago, IL, USA;9. Department of Biology, University of North Carolina, Chapel Hill, NC, USA |
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| 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. |
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| Keywords: | Chromatin accessibility Chronic inflammation IL‐10 Inflammatory bowel disease Macrophages |
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