Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

Abstract

Toll-like receptor signaling and subsequent activation of NF-κB-and MAPK-dependent genes during infection play an important role in antimicrobial host defense. The YopJ protein of pathogenic Yersinia species inhibits NF-κB and MAPK signaling, resulting in blockade of NF-κB-dependent cytokine production and target cell death. Nevertheless, Yersinia infection induces inflammatory responses in vivo. Moreover, increasing the extent of YopJ-dependent cytotoxicity induced by Yersinia pestis and Yersinia pseudotuberculosis paradoxically leads to decreased virulence in vivo, suggesting that cell death promotes anti-Yersinia host defense. However, the specific pathways responsible for YopJ-induced cell death and how this cell death mediates immune defense against Yersinia remain poorly defined. YopJ activity induces processing of multiple caspases, including caspase-1, independently of inflammasome components or the adaptor protein ASC. Unexpectedly, caspase-1 activation in response to the activity of YopJ required caspase-8, receptor-interacting serine/threonine kinase 1 (RIPK1), and Fas-associated death domain (FADD), but not RIPK3. Furthermore, whereas RIPK3 deficiency did not affect YopJ-induced cell death or caspase-1 activation, deficiency of both RIPK3 and caspase-8 or FADD completely abrogated Yersinia-induced cell death and caspase-1 activation. Mice lacking RIPK3 and caspase-8 in their hematopoietic compartment showed extreme susceptibility to Yersinia and were deficient in monocyte and neutrophil-derived production of proinflammatory cytokines. Our data demonstrate for the first time to our knowledge that RIPK1, FADD, and caspase-8 are required for YopJ-induced cell death and caspase-1 activation and suggest that caspase-8-mediated cell death overrides blockade of immune signaling by YopJ to promote anti-Yersinia immune defense.innate immunity | apoptosis | programmed necrosis | macrophage | pyroptosis

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

“…49 Although caspase 1/11 signaling promotes canonical inflammasome signaling, caspase 8 and other members of the ripoptosome complex have also been shown to promote inflammasome activation. [50][51][52][53][54] Our results show that caspase 8 activity was reduced in RIPK1 K45A macrophages, which may limit IL-1β processing in RIPK1 K45A macrophages. We observed that the activity of caspase 8 was reduced in macrophages following infection with ST. Interestingly, caspase 1, which is activated during infection with ST, has been previously shown to limit the processing of various caspases.…”

“…9,56 Although RIPK3 is a key component of the necrosome complex, and we have previously shown that RIPK3 is activated following ST infection, 57 RIPK3 has also been shown to promote inflammasome signaling. 11,50,51,53 More recently, MLKL, another member of the necrosome, has also been shown to promote inflammasome signaling, 58 indicating that there is significant overlap in inflammasome and necrosome signaling. We have previously shown that WT and RipK3 − / − mice harbor similar bacterial burden at day 5 postinfection with ST, 57 whereas, in our current study, the bacterial burden in RIPK1…”

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.…”

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

“…However, Yersinia also inhibits inflammasome activation through the activities of YopK and YopM (36,38,39). Recent studies have revealed that YopJ can cooperate with YopM in activated macrophages to limit inflammasome activation (78,81), although YopJ blockade of NF-B and MAPK signaling triggers the activation of caspase-8 and caspase-1 in naive macrophages (82,83).…”