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Myeloid p38? signaling promotes intestinal IGF-1 production and inflammation-associated tumorigenesis.

ABSTRACT: The protein kinase p38? plays a key role in cell homeostasis, and p38? signaling in intestinal epithelial cells protects against colitis-induced tumorigenesis. However, little is known on the contribution of p38? signaling in intestinal stromal cells. Here, we show that myeloid cell-specific downregulation of p38? protects mice against inflammation-associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recruitment. We identify insulin-like growth factor-1 (IGF-1) as a novel mediator of the p38? pathway in macrophages. Moreover, using genetic and pharmacological approaches, we confirm the implication of IGF-1 produced by myeloid cells in colon inflammation and tumorigenesis. We also show a correlation between IGF-1 pathway activation and the infiltration of myeloid cells with active p38? in colon samples from patients with ulcerative colitis or colon cancer. Altogether, our results uncover an important role for myeloid IGF-1 downstream of p38? in colitis-associated tumorigenesis and suggest the interest in evaluating IGF-1 therapies for inflammation-associated intestinal diseases, taking into consideration IGF-1 signaling and immune cell infiltration in patient biopsies.

SUBMITTER: Youssif C

PROVIDER: S-EPMC6034132 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Myeloid p38α signaling promotes intestinal IGF-1 production and inflammation-associated tumorigenesis.

Youssif Catrin C Cubillos-Rojas Monica M Comalada Mònica M Llonch Elisabeth E Perna Cristian C Djouder Nabil N Nebreda Angel R AR

EMBO molecular medicine 20180701 7

The protein kinase p38α plays a key role in cell homeostasis, and p38α signaling in intestinal epithelial cells protects against colitis-induced tumorigenesis. However, little is known on the contribution of p38α signaling in intestinal stromal cells. Here, we show that myeloid cell-specific downregulation of p38α protects mice against inflammation-associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recru ...[more]

PMID: 29907597

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Project description:Background & aimsWe previously showed that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells.MethodsAnalyses using online databases of single-cell RNA sequencing of intestinal epithelial cells in mice and RNA sequencing of mouse immune cells were performed to determine the relative abundances of 4 histamine receptors among different cell types. Mouse neutrophils, which expressed greater amounts of H2R, were collected from the peritoneum of wild-type and H2R-deficient mice, of which low-density and high-density neutrophils were extracted by centrifugation and were subjected to RNA sequencing. The effects of H2R activation on neutrophil differentiation and its functions in colitis and inflammation-associated colon tumors were investigated in a mouse model of dextran sulfate sodium-induced colitis.ResultsData analysis of RNA sequencing and quantitative reverse-transcription polymerase chain reaction showed that Hrh2 is highly expressed in neutrophils, but barely detectable in intestinal epithelial cells. In mice, the absence of H2R activation promoted infiltration of neutrophils into both sites of inflammation and colonic tumors. H2R-deficient high-density neutrophils yielded proinflammatory features via nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and suppressed T-cell proliferation. On the other hand, low-density neutrophils, which totally lack H2R activation, showed an immature phenotype compared with wild-type low-density neutrophils, with enhanced MYC pathway signaling and reduced expression of the maturation marker Toll-like receptor 4.ConclusionsBlocking H2R signaling enhanced proinflammatory responses of mature neutrophils and suppressed neutrophil maturation, leading to accelerated progression of inflammation-associated colonic tumorigenesis.

Dataset Information

Myeloid p38? signaling promotes intestinal IGF-1 production and inflammation-associated tumorigenesis.

Publications

Myeloid p38α signaling promotes intestinal IGF-1 production and inflammation-associated tumorigenesis.

Similar Datasets

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