Myeloid Cell-Specific Deletion of PDGFR-α Promotes Dysbiotic Intestinal Microbiota and thus Increased Colitis Susceptibility.

Abstract

The incidence of inflammatory bowel diseases [IBD] is steadily increasing, and thus the identification of new targets to improve therapy is a major goal. Growth factors of the PDGF family and their receptors are expressed early in intestinal development and are found in mononuclear cells and macrophages in adult tissues. Macrophages play a distinct role in the pathogenesis of IBD since their function is crucial to maintaining tolerance. We aimed to study the role of myeloid expression of PDGFR-α in mediating intestinal homeostasis in mouse IBD and infectious models. Our results show that loss of myeloid PDGFR-α increases susceptibility to dextran saline sulphate-induced colitis. Accordingly, LysM-PDGFR-α-/- mice showed higher colitis scores, and reduced levels of anti-inflammatory macrophages compared to control mice. This effect was mediated via a pro-colitogenic microbiota, which developed in the absence of myeloid PDGFR-α and caused increased colitis susceptibility in gnotobiotic mice upon faecal microbiota transplantation compared to controls. Furthermore, LysM-PDGFR-α-/- mice had a leaky gut, accompanied by impaired phagocytosis, resulting in a severe barrier defect. Taken together, our results indicate a protective role for myeloid PDGFR-α in maintaining gut homeostasis by promoting a protective intestinal microbiota and providing an anti-inflammatory macrophage phenotype.