NLRP3 inflammasome activation triggers gasdermin D–independent inflammation

Wang, Chun; Yang, Tong; Xiao, Jianqiu; Xu, Chenghai; Alippe, Yael; Sun, Kai; Kanneganti, Thirumala‐Devi; Monahan, Joseph B.; Abu‐Amer, Yousef; Lieberman, Judy; Mbalaviele, Gabriel

doi:10.1126/sciimmunol.abj3859

Cited by 155 publications

(109 citation statements)

References 85 publications

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“…Indeed, the phenotype of either single mutant strain implied non-redundant functions of both GSDMs whereas the outcomes of compound mutants suggested that they shared downstream effector molecules. The latter view was supported by the ability of either GSDM to mediate pyroptosis and IL-1β and IL-18 release in cell a context-dependent manner (35,(37)(38)(39)(40). Furthermore, functional complementation of GSDMD by GSDME has also been reported (35).…”

Section: Discussionmentioning

confidence: 98%

“…The latter view was supported by the ability of either GSDM to mediate pyroptosis and IL-1β and IL-18 release in cell a context-dependent manner (35,(37)(38)(39)(40). Furthermore, functional complementation of GSDMD by GSDME has also been reported (35). Thus, although additional studies are needed for further insights onto the mechanism of differential actions of GSDMD and GSDME in bone recovery after injury, our findings reinforce the crucial role that inflammation plays during the bone fracture healing process.…”

Section: Discussionmentioning

confidence: 98%

“…GSDMD is also involved in the pathogenesis of complex diseases including experimental autoimmune encephalitis, radiation-induced tissue injury, ischemia/reperfusion injury, sepsis, renal fibrosis, and thrombosis (28)(29)(30)(31)(32)(33). Other well studied GSDMs include GSDMA and GSDME (25,(34)(35)(36). GSDME is of particular interest to this study because recent evidence suggests that it harbors overlapping and non-overlapping actions with GSDMD, depending on cell contexts.…”

Section: Introductionmentioning

confidence: 99%

“…GSDME is of particular interest to this study because recent evidence suggests that it harbors overlapping and non-overlapping actions with GSDMD, depending on cell contexts. Indeed, GSDME can mediate pyroptosis and release cytokines under both GSDMD sufficient and insufficient conditions (35,(37)(38)(39)(40). Despite advances in GSDM studies, the role that these proteins play in fracture healing has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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Fracture healing is delayed in the absence of gasdermin signaling

Mbalaviele

Sun

Wang

et al. 2021

Preprint

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Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM- mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fracture healing is delayed in the absence of gasdermin signaling

Mbalaviele

Sun

Wang

et al. 2021

Preprint

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“…GSDMD is also involved in the pathogenesis of complex diseases including experimental autoimmune encephalitis, radiation-induced tissue injury, ischemia/reperfusion injury, sepsis, renal fibrosis, and thrombosis ( Li et al, 2019 ; Xiao et al, 2020 ; Zhang et al, 2019 ; Silva et al, 2021 ; Zhang et al, 2021c ; Zhang et al, 2021a ). Other well-studied GSDMs include GSDMA and GSDME ( Liu et al, 2021 ; Zhang et al, 2020 ; Wang et al, 2021 ; Zhou et al, 2020 ). GSDME is of particular interest to this study because recent evidence suggests that it harbors overlapping and non-overlapping actions with GSDMD, depending on cell contexts.…”

Section: Introductionmentioning

confidence: 99%

Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling

Sun

Chün²,

Xiao³

et al. 2022

eLife

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IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture.

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Gasdermin‐E‐Dependent Non‐Canonical Pyroptosis Promotes Drug‐Induced Liver Failure by Promoting CPS1 deISGylation and Degradation

Ouyang,

Zhu,

Cao

et al. 2024

Advanced Science

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Drug‐induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non‐canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP‐DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP‐DILI. Mice with hepatocyte‐specific rescue of GSDME reproduced APAP‐induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP‐induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte‐derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte‐specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon‐stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase‐1 (CPS1), promoted its degradation via K48‐linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl‐fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP‐DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP‐DILI.

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NLRP3 inflammasome activation triggers gasdermin D–independent inflammation

Abstract: Sustained stimulation of the NLRP3 inflammasome causes inflammation in the absence of GSDMD.

Cited by 155 publications

References 85 publications

Fracture healing is delayed in the absence of gasdermin signaling

Fracture healing is delayed in the absence of gasdermin signaling

Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling

Gasdermin‐E‐Dependent Non‐Canonical Pyroptosis Promotes Drug‐Induced Liver Failure by Promoting CPS1 deISGylation and Degradation

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