Receptor-interacting protein 2 (RIP2) is a kinase which mediates signaling downstream of the bacterial peptidoglycan sensors Nucleotide-binding Oligomerization Domain (NOD) 1 and 2. Genetic loss or pharmaceutical inhibition of RIP2 has been shown to be beneficial in multiple inflammatory disease models with the effects largely attributed to reducing pro-inflammatory signaling downstream of peptidoglycan recognition. However, given the widespread expression of this kinase and its reported interactions with numerous other proteins, it is possible that RIP2 has many other unappreciated roles. In this work, we report the involvement of RIP2 in two novel pathways. First, we demonstrate a NOD2 dependent role for RIP2 in mediating ROS production downstream of FcƴR engagement. In these studies, we show that different members of the Src family kinases (SFKs) can promote RIP2 tyrosine phosphorylation and activation, providing a potential mechanism for such involvement. Second, we discover a novel role for RIP2 in the production of specialized pro-resolving lipid mediators (SPMs). SPMs are biologically active mediators which promote resolution by dampening the inflammatory immune response and enhancing the return to homeostasis. We show that NOD2 agonism leads to RIP2-dependent production of different SPMs in an in vivo murine peritonitis model. Using overexpression studies, we demonstrate that RIP2 promotes the modification and relocalization of various enzymes involved in SPM biosynthesis. Overall, our findings shed light on novel functional roles for NOD2 and RIP2 outside of peptidoglycan sensing. These data will have important implications for newly developing RIP2 targeted therapies by potentially determining the molecular basis for in vivo efficacy (or lack thereof) as well as elucidating a potential optimal therapeutic window for administration of such therapies for treatment of various inflammatory diseases.
Doctor of Philosophy (Ph.D.)
College of Medicine
Length of Campus-only Access
Doctoral Dissertation (Campus-only Access)
Shehat, Michael, "Novel Roles of RIP2 in Inflammation and Resolution" (2020). Electronic Theses and Dissertations, 2020-. 455.