Necroptosis-independent signaling by the RIP kinases in inflammation

Abstract

Recent advances have identified a signaling cascade involving receptor interacting protein kinase 1 (RIPK1), RIPK3 and the pseudokinase mixed lineage kinase domain-like (MLKL) that is crucial for induction of necroptosis, a non-apoptotic form of cell death. RIPK1-RIPK3-MLKL-mediated necroptosis has been attributed to cause many inflammatory diseases through the release of cellular damage-associated molecular patterns (DAMPs). In addition to necroptosis, emerging evidence suggests that these necroptosis signal adaptors can also facilitate inflammation independent of cell death. In particular, the RIP kinases can drive NF-κB and inflammasome activation independent of cell death. In this review, we will discuss recent discoveries that led to this realization and present arguments why cell death-independent signaling by the RIP kinases may have a more important role in inflammation than necroptosis.

Keywords: IL-1β; NF-κB; RIPK1; RIPK3; RelB.

Fig. 1

The different modes of RIPK3-mediated NLRP3 inflammasome activation. a In BMDCs, RIPK3 promotes activation of caspase 1 (C1) in response to LPS alone, possibly through ROS production. In addition to caspase 1, RIPK3 promotes caspase 8 activation through the ripoptosome, which directly cleaves pro-IL-1β. b Depletion of IAP proteins induces IL-1β secretion through robust activation of caspase 1 and caspase 8 in LPS-primed BMDMs and BMDCs. In contrast to necroptosis, the kinase activities of RIPK1 and RIPK3 are dispensable for pro-IL-1β processing through caspase 1 and caspase 8. However, when caspase 8 (C8) activity is blocked, the RIPK3 kinase activity and MLKL becomes essential to stimulate the NLRP3 inflammasome activation. c In BMDMs, poly(I:C) treatment stimulates TLR3 and TRIF, leading to FADD, RIPK1 and caspase 8 (C8)-dependent NLRP3 inflammasome activation. RIPK3 is not required for this response. However, when caspase 8 activity is blocked, RIPK3 kinase activity and MLKL phosphorylation become essential for NLRP3 inflammasome activation. In addition, RIPK3-dependent NLRP3 inflammasome activation requires caspase 8 scaffold function, since TLR3 can no longer stimulate NLRP3 inflammasome when caspase 8 is missing. d LPS-primed caspase 8 or FADD-deficient BMDCs produce increased levels of IL-1β through enhanced caspase 1 activation. This response requires RIPK1 and RIPK3 kinase activities and MLKL. MLKL activation through the RIPK3 kinase activity may directly activate the NLRP3 inflammasome. Alternatively, MLKL might enhance necroptosis, leading to DAMPs release or K⁺ efflux [102] and subsequent NLRP3 inflammasome activation. P in a circle indicates that the kinase activity of RIPK1 or RIPK3 is required