Alterations to chromatin in intestinal macrophages link IL‐10 deficiency to inappropriate inflammatory responses

Abstract

Intestinal macrophages 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 intestinal macrophage 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 mice. In both bone-marrow-derived and intestinal macrophages, we identified chromatin accessibility changes associated with bacterial exposure and IL-10-deficiency. Surprisingly, IL-10-deficient intestinal macrophages adopted chromatin and gene expression patterns characteristic of an inflammatory response, even in the absence of bacteria. Further, if IL-10 protein was added to cells that had previously been IL-10-deficient, 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 where IL-10-deficiency leads to chromatin alterations that contribute to a loss of intestinal macrophage tolerance to bacteria, which is a primary initiating event in chronic intestinal inflammation.

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

“…However, consistent with previous findings, the IL-10 effect was most prominent in repression of LPS-induced inflammatory genes (Gopinathan et al, 2012;Lang et al, 2002a;Murray, 2005), possibly through epigenetic mechanisms Kobayashi et al, 2012;Simon et al, 2016). In addition, IL-10 also induced expression of LPS-repressed genes including those related to carbohydrate and lipid metabolism, in line with a recent report that the anti-inflammatory effects of IL-10 involve metabolic reprogramming of Mφs (Ip et al, 2017).…”

Molecular classification of Crohn's disease reveals two clinically relevant subtypes

“…Chromatin profiling provides a mechanism as to why expression is changing, and whether observed changes may be transient or persistent. We have shown that chromatin accessibility can differentiate disease subtypes[10] and helps to describe genetic and environmental contributors to disease[11]. We therefore sought to determine whether multiple clinically distinct subclasses of adult CD exist by examining both gene expression, using RNA-seq, and chromatin accessibility, using Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE-seq)[12], in CD and non-IBD patient samples of unaffected colon mucosa.…”

Gene regulatory mechanisms underlying the intestinal innate immune response

“…The gene regulatory mechanisms controlling this behavior have been recently examined, revealing that the chromatin accessibility landscape of IL-10 knockout intestinal macrophages was similar to that of inflammatory macrophages. This finding suggests that IL-10-deficiency alone is sufficient to poise chromatin for an inflammatory response [35]. Overall, this extensive crosstalk between the microenvironment, LDTFs and SDTFs allows macrophages to control signal-specific transcriptional outputs that are important for their respective tissue of residency [6 ,7 ].…”