Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death

Abstract

A number of pathogens cause host cell death upon infection, and Yersinia pestis, infamous for its role in large pandemics such as the "Black Death" in medieval Europe, induces considerable cytotoxicity. The rapid killing of macrophages induced by Y. pestis, dependent upon type III secretion system effector Yersinia outer protein J (YopJ), is minimally affected by the absence of caspase-1, caspase-11, Fas ligand, and TNF. Caspase-8 is known to mediate apoptotic death in response to infection with several viruses and to regulate programmed necrosis (necroptosis), but its role in bacterially induced cell death is poorly understood. Here we provide genetic evidence for a receptor-interacting protein (RIP) kinasecaspase-8-dependent macrophage apoptotic death pathway after infection with Y. pestis, influenced by Toll-like receptor 4-TIR-domain-containing adapter-inducing interferon-β (TLR4-TRIF). Interestingly, macrophages lacking either RIP1, or caspase-8 and RIP3, also had reduced infection-induced production of IL-1β, IL-18, TNF, and IL-6; impaired activation of the transcription factor NF-κB; and greatly compromised caspase-1 processing. Cleavage of the proform of caspase-1 is associated with triggering inflammasome activity, which leads to the maturation of IL-1β and IL-18, cytokines important to host responses against Y. pestis and many other infectious agents. Our results identify a RIP1-caspase-8/RIP3-dependent caspase-1 activation pathway after Y. pestis challenge. Mice defective in caspase-8 and RIP3 were also highly susceptible to infection and displayed reduced proinflammatory cytokines and myeloid cell death. We propose that caspase-8 and the RIP kinases are key regulators of macrophage cell death, NF-κB and inflammasome activation, and host resistance after Y. pestis infection.

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

“…Myeloid cells can undergo necroptosis in response to a variety of pathogenic signals. 27,40 Hence, future studies must address the possible contribution of chemotherapy-induced necroptosis in inflammatory and immune cells in anticancer immunosurveillance. Irrespective of this limitation, the present data support the notion that RIP3 and MLKL may participate to chemotherapy-induced ICD.…”

RIP kinases: key decision makers in cell death and innate immunity

“…However, the role of caspase 8 is complex and context dependent as the causative agent of plague Yersinia pestis and its outer protein YopJ employs caspase 8, RIP1 and RIP3 to trigger cell death and caspase 1 activation. 123,124 Interestingly, another study demonstrated that pharmacological or genetic depletion of the cIAP proteins in macrophages, in conjunction with TLR stimulation, resulted in augmented processing of pro-IL-1b into its mature form. 125 The processing of IL-1b was driven by two independent pathways involving NLRP3/caspase 1 and caspase 8.…”

Receptor interacting protein kinase 1 (RIPK1) in hepatocytes does not mediate murine acetaminophen toxicity

“…It cannot be excluded that other intra-and extrahepatic cell compartments than hepatocytes-such as monocytes or T cells-are targeted by repetitive injections of antisense oligonucleotides. (3) Of note, macrophages lacking Ripk1 show reduced cytokine production, impaired nuclear factor kappa B activation, and greatly compromised caspase 1 processing, (4) which might contribute to the beneficial effects upon oligomer injections. (2) This would also explain the similarity between the findings from Dara et al and previous results using the chemical inhibitor Nec-1 in the acetaminophen model.…”