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

Abstract

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 recruitment. We identify insulin‐like growth factor‐1 (IGF‐1) as a novel mediator of the p38α 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 p38α in colon samples from patients with ulcerative colitis or colon cancer. Altogether, our results uncover an important role for myeloid IGF‐1 downstream of p38α 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.

NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis

“…27 Much like DSS-treated mNAIL ΔNFκB mice, the colitis model of p38 KO mice show reduced levels of Ly6C hi cells in bone marrow which results in less F4/80 infiltration to the colon. 23 Importantly, our results showed that mNAIL is not induced in intestinal epithelial cells and there is no difference in TNFα expression between mNAIL WT and mNAIL ΔNFκB mice (online supplemental figure 7A,B). These results showed that BMDMs are possibly the major source of mNAIL expression and phenotypes seen may stem from these cells, we performed bone marrow transplantation followed by DSS stimulation (figure 6D).…”

“…18 19 Especially, monocytes derived from the CD11b+Ly6C hi Ly6G− immature myeloid cells have been shown to enter tissues under inflammatory conditions and express high levels of proinflammatory cytokines in colitis. [20][21][22] Given that myeloid cells are the predominant cells that infiltrate the inflamed tissues and the precursors are made in bone marrow, 23 we analysed the myeloid populations in the bone marrow of mNAIL ΔNFκB mice. As expected, both mNAIL WT and mNAIL ΔNFκB mice showed increased CD11b+population, on DSS treatment (figure 3E-G).…”

Long-term Inflammatory Stimulation Caused by Trauma May Lead to Jejunum Intestinal Stromal Tumor: A Case Report

“…Theodoropoulos GE et al [15]reported that a patient with ulcerative colitis was diagnosed with GIST after surgery due to jejunoileum intussusception, but another study found that patients with in ammatory bowel disease (IBD) had an increased risk of cancer, especially it is for patients taking immunosuppressive agents [16]. Most cancers occur in the site of in ammation and have experienced the sequence of in ammationdysplasia-cancer [17,18]. Many studies [18,19]reported that some in ammatory factors can change the tumor microenvironment and promote tumor survival.…”

“…Most cancers occur in the site of in ammation and have experienced the sequence of in ammationdysplasia-cancer [17,18]. Many studies [18,19]reported that some in ammatory factors can change the tumor microenvironment and promote tumor survival. Cavnar MJ.…”

Diet, Microbiota, and Colorectal Cancer

“…Importantly, it has been shown that reducing inflammation protects from inflammation-associated colon tumorigenesis. In this regard, genetic ablation of p38α in intestinal tissue (involved in the regulation of cytokine production and inflammatory responses) ameliorates tumor formation and protects against inflammation-associated colon tumorigenesis (Youssif et al., 2018).…”