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

The protein kinase p38 alpha plays a key role in cell homeostasis, and p38 alpha signaling in intestinal epithelial cells protects against colitis-induced tumorigenesis. However, little is known on the contribution of p38 alpha signaling in intestinal stromal cells. Here, we show that myeloid cell-specific downregulation of p38 alpha 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 alpha 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 alpha 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 alpha 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.