SRP060349 PRJNA288935 GSE70517 Alterations to chromatin in intestinal macrophages link IL-10 deficiency to inappropriate inflammatory responses 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 (BMMs) 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. Overall design: Investigation of chromatin accessibility and gene expression changes in response to bacteria, and how these responses are altered in the absence of IL-10 GSE70517 pubmed 27159132