RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

TLDR

"The study investigates whether RIPK3 can promote inflammation independently of MLKL-mediated necroptosis." Findings: Summarize all findings: LPS triggers RIPK3 to activate caspase-8 and NLRP3–caspase-1 independent of RIPK3 kinase activity and MLKL when IAPs absent; in absence of IAPs and caspase-8, RIPK3 kinase activity and MLKL needed for TLR-induced NLRP3 activation; IL-1 dependent arthritis worsened in IAP-deficient mice, reduced by RIPK3 deletion but not MLKL; overall RIPK3 promotes NLRP3 inflammasome and IL-1β responses independent of MLKL and necroptotic cell death. Let's craft: "In IAP-deficient cells, LPS activates RIPK3 to trigger caspase‑8–mediated apoptosis and NLRP3–caspase‑1 inflammasome activation without requiring RIPK3 kinase activity or MLKL, whereas when both IAPs and caspase‑8 are absent, RIPK3 kinase activity and MLKL become essential for TLR‑induced NLRP3 activation; in vivo, IL‑1–dependent arthritis is exacerbated by loss of IAPs and mitigated by RIPK3 deletion but not MLKL, demonstrating that RIPK3 can drive NLRP3 inflammasome and IL‑1β responses independently of MLKL and necroptotic cell death." Check length: It's long but still one sentence. Ensure no semicolons?

Abstract

Abstract RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3–caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death.