Targeting RIPK1,2,3 to combat inflammation.

Receptor Interacting Protein Kinases (RIPKs) are a seven member family of human dual specificity (Ser/Thr and Tyr) kinases. Several members of this family, namely RIPK1, RIPK2, RIPK3 and RIPK7/LRRK2, have been implicated in human disease. However, besides RIPK1 and RIPK3, few commonalities have emerged with respect to the functional roles of these kinases. In this letter, we discuss recent work suggesting common themes in the cellular pathways regulated by RIPK1/3 and RIPK2 that may be relevant for the development of new therapeutic approaches against human inflammatory pathologies. RIPK1 and RIPK3 kinase activities have been linked to the process of regulated necrotic cell death or " necroptosis " , which contributes to a variety of necrotic injuries in vivo (reviewed further in [1]). Furthermore, these kinases combine to form the " necrosome " complex when stimulated by Tumor Necrosis Factor alpha (TNFα). In contrast, RIPK2 mediates pro-inflammatory signaling from the bacterial peptidoglycan-sensing NOD1/2 sub-family of innate immune Pattern Recognition Receptors (PRRs) and is a putative contributor to a range of chronic inflammatory granulomatous diseases, including Inflammatory Bowel Disease (IBD) (reviewed further in [2]). However, new small molecule and genetic tools have enhanced our understanding of the functions and regulation of these kinases revealing potential common themes in the functions of RIPK1/3 and RIPK2. First, it became clear that RIPK1 and RIPK3, similarly to RIPK2, may function in the context of the innate immune responses by signaling downstream from the Toll-like receptor (TLR) family of PRRs (reviewed further in [3]). Furthermore, the IAP family E3 ubiquitin ligases, which have critical roles in innate immunity, can target both RIPK1/3 and RIPK2 suggesting further possibility of coordinate regulation. Second, while RIPK1/3 may primarily function as pro-death kinases, their activity in vivo leads to the robust induction of inflammation, reflecting the pro-inflammatory nature of necrotic cell death as well as still poorly understood cell death-independent inflammatory signaling by these kinases [3]. Third, both RIPK1 and RIPK2 have now emerged as critical mediators of intestinal homeostasis and drivers of intestinal inflammation. In the case of RIPK2, both loss-of-function of NOD2 and hyperactivation of this pathway may contribute to IBD (reviewed further in [2]). Similarly, loss of RIPK1 protein and hyperactivation of RIPK1 catalytic activity have both now been linked to the development of intestinal inflammation through the cell death-mediated loss of epithelial barrier function [4]. Moreover, perturbations in intestinal homeostasis in response to alterations in both …