Inflammatory bowel diseases (IBD) are relapsing disorders of the gastrointestinal tract characterized by chronic inflammation of the intestinal mucosa and tissue damage. Current pharmacological approaches in IBD primarily focus on dampening the inflammatory immune response. However, IBD is often associated with deficient or pathological tissue repair such as ulcers or fistulas and intestinal fibrosis or strictures. Therefore, understanding the mechanisms that promote tissue repair and physiological regeneration of the intestine is of outstanding importance towards the development of improved therapies in IBD. Macrophages have a fundamental role in inflammation as well as in tissue repair. While classically activated macrophages (M1) predominate during inflammation, the resolution of inflammation and intestinal wound healing is dependent on the transition of macrophages into an alternative, tissue repair (M2) state. We propose that the Axl and Mer (AM) receptor tyrosine kinases coordinate the phasing out from the M1 with the induction of the M2 response. We propose to (i) identify the molecular mechanism by which AM RTK signaling induces M2-macrophage polarization, (ii) identify the intestinal macrophage population in which the AM RTK signaling pathway coordinates the M1 to M2 switch to limit inflammation and induce tissue repair in the gut, and (iii) validate the AM pathway as a novel target for the combinatorial suppression of inflammation and induction of tissue repair in mouse models of injury in the gut. Unraveling the mechanism by which the AM pathway shapes macrophage polarization, ensuring effective silencing of the inflammatory state, together with the induction o the tissue repair program and obtaining proof-of-concept for engaging the AM RTKs in mouse models of intestinal injury will (1) significantly advance our knowledge on mucosal homeostasis and (2) pave the way for translational studies towards new and improved treatments in IBD.
Inflammatory bowel diseases (IBD) are relapsing disorders of the gastrointestinal tract characterized by chronic inflammation of the intestine and tissue damage. Complete remission requires both the cessation of the pathological inflammatory response as well as the active removal of dead cells and their physiological replacement by the same cell types in order to preserve organ function. Here we will investigate the role of a family of receptors, TAM receptor tyrosine kinases, in coordinating the suppression of inflammation and induction of tissue repair responses towards the development of improved treatments in IBD.
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