Unknown,Transcriptomics,Genomics,Proteomics

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IL-10 from intestinal macrophages prevents excessive innate immune responses to bacteria by limiting IL-23 synthesis


ABSTRACT: Innate immune responses must be regulated in the intestine to prevent excessive inflammation. Here, using gene reporter mice, we show that a subset of mouse colonic macrophages constitutively produced the anti-inflammatory cytokine IL-10. In mice infected with Citrobacter rodentium, which is considered similar to enteropathogenic Escherichia coli infection in humans, macrophage IL-10 was required to prevent intestinal pathology and to promote survival. The synthesis of the proinflammatory cytokine IL-23 was significantly increased in infected mice with a myeloid cell specific deletion of IL-10 and the addition of IL-10 reduced in vitro IL-23 production by intestinal macrophages. Furthermore, blockade of IL-23 led to reduced morbidity and mortality in the context of macrophage IL-10 deficiency. Transcriptome analysis indicated that the reporter positive and negative colonic macrophage subsets were highly similar, but the reporter positive cells differed for the expression of CD163, an IL-10 target gene, suggesting an autocrine IL-10 signal, and when obtained from infected mice, they had reduced IL-23p19 mRNA. Interestingly, only transfer of the reporter positive cells could rescue IL-10 deficient infected mice. Therefore, these data indicate a pivotal role for a subset of intestinal macrophages that constitutively produces IL-10, perhaps acting in part in autocrine fashion, in controlling excessive innate immune activation, regulation of IL-23 production, and prevention of tissue damage after an acute bacterial infection in the intestine. Two replicates each of IL10+ and IL10- large intestinal macrophages. Data were normalized with the 'rma' function of the Bioconductor package, along with several GEO (GSM616132, GSM616136, GSM616140, GSM868296, GSM868297, GSM868298) and ArrayExpress (E-MEXP-3216: 04-M2WT, 05-M2WT, 06-M2WT) datasets.

ORGANISM(S): Mus musculus

SUBMITTER: Jason Greenbaum 

PROVIDER: E-GEOD-58677 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis.

Krause Petra P   Morris Venetia V   Greenbaum Jason A JA   Park Yoon Y   Bjoerheden Unni U   Mikulski Zbigniew Z   Muffley Tracy T   Shui Jr-Wen JW   Kim Gisen G   Cheroutre Hilde H   Liu Yun-Cai YC   Peters Bjoern B   Kronenberg Mitchell M   Murai Masako M  

Nature communications 20150511


Innate immune responses are regulated in the intestine to prevent excessive inflammation. Here we show that a subset of mouse colonic macrophages constitutively produce the anti-inflammatory cytokine IL-10. In mice infected with Citrobacter rodentium, a model for enteropathogenic Escherichia coli infection in humans, these macrophages are required to prevent intestinal pathology. IL-23 is significantly increased in infected mice with a myeloid cell-specific deletion of IL-10, and the addition of  ...[more]

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