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.
|Chan, Pamela Y; Carrera Silva, Eugenio A; De Kouchkovsky, Dimitri et al. (2016) The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352:99-103|
|Chae, Wook-Jin; Ehrlich, Allison K; Chan, Pamela Y et al. (2016) The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 44:246-58|
|Fourgeaud, Lawrence; TravÃ©s, Paqui G; Tufail, Yusuf et al. (2016) TAM receptors regulate multiple features of microglial physiology. Nature 532:240-4|
|Rothlin, Carla V; Carrera-Silva, Eugenio A; Bosurgi, Lidia et al. (2015) TAM receptor signaling in immune homeostasis. Annu Rev Immunol 33:355-91|
|BÃ¡rcena, Cristina; Stefanovic, Milica; Tutusaus, Anna et al. (2015) Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J Hepatol 63:670-8|
|CabezÃ³n, Raquel; Carrera-Silva, E Antonio; FlÃ³rez-Grau, Georgina et al. (2015) MERTK as negative regulator of human T cell activation. J Leukoc Biol 97:751-60|
|Rothlin, Carla V; Leighton, Jonathan A; Ghosh, Sourav (2014) Tyro3, Axl, and Mertk receptor signaling in inflammatory bowel disease and colitis-associated cancer. Inflamm Bowel Dis 20:1472-80|
|Kusne, Yael; Carrera-Silva, Eugenio A; Perry, Anthony S et al. (2014) Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFÎ± in glioblastoma. Sci Signal 7:ra75|
|van den Brand, B T; Abdollahi-Roodsaz, S; Vermeij, E A et al. (2013) Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis. Arthritis Rheum 65:671-80|
|Bhattacharyya, Suchita; Zagorska, Anna; Lew, Erin D et al. (2013) Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe 14:136-47|
Showing the most recent 10 out of 13 publications