Indirect regulation of HMGB1 release by gasdermin D

Volchuk, Allen; Ye, Anna; Chi, Leon; Steinberg, Benjamin E.; Goldenberg, Neil M.

doi:10.1038/s41467-020-18443-3

Cited by 144 publications

(111 citation statements)

References 60 publications

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“…In the spiral ligament, we found that the tendency of AFD elevated ( Figures 3C,D ), which was consistent with the change in the total cochlear level of HMGB1 ( Figure 1B ). Necroptosis-, ferroptosis-, apoptosis- and pyroptosis-mediated mechanism have all been implicated in HMGB1 release from cells ( Scaffidi et al, 2002 ; Bell et al, 2006 ; Murai et al, 2018 ; Wen et al, 2019 ; Volchuk et al, 2020 ). Specifically, as a marker of cellular damage, the increasing HMGB1 level or the release of HMGB1 in the spiral ligament indicated the activation of cell death pathways.…”

Section: Discussionmentioning

confidence: 99%

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

Xiao

Sun

Liu

et al. 2021

Front. Cell Dev. Biol.

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Noise-induced hearing loss (NIHL) is characterized by cellular damage to the inner ear, which is exacerbated by inflammation. High-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP), acts as a mediator of inflammation or an intercellular messenger according to its cellular localization. Blocking or regulating HMGB1 offers an attractive approach in ameliorating NIHL. However, the precise therapeutic intervention must be based on a deeper understanding of its dynamic molecular distribution and function in cochlear pathogenesis after acoustic trauma. Here, we have presented the spatiotemporal dynamics of the expression of HMGB1, exhibiting distribution variability in specific cochlear regions and cells following noise exposure. After gene manipulation, we further investigated the characteristics of cellular HMGB1 in HEI-OC1 cells. The higher cell viability observed in the HMGB1 knocked-down group after stimulation with H2O2 indicated the possible negative effect of HMGB1 on cellular lifespan. In conclusion, this study demonstrated that HMGB1 is involved in NIHL pathogenesis and its molecular biology has essential and subtle influences, preserving a translational potential for pharmacological intervention.

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Section: Discussionmentioning

confidence: 99%

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

Xiao

Sun

Liu

et al. 2021

Front. Cell Dev. Biol.

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“… 113 In more advanced stages, GSDMD pores lead to membrane destabilization and cell lysis, enabling the release of DAMPs such as HMGB1 that are too large to escape the cell through the pores. 114 Adding to the complexity of pyroptosis, several additional caspases are implicated in a noncanonical pathway, directly targeting GSDMD for cleavage. Murine caspase-11 was first described as a caspase-1 interactor more than two decades ago.…”

Section: Pyroptosis: a Master Regulator Of Inflammationmentioning

confidence: 99%

Necroptosis, pyroptosis and apoptosis: an intricate game of cell death

2021

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Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as ‘programmed cell death’ have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies have highlighted the complex mechanisms tipping the balance between different cell fates. Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.

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“…It is worth noting that there was some residual IL-1β release and pyroptosis even in Gsdmd -/- ; Gsdme -/- BMDMs, suggesting that another GSDMD and GSDME independent inflammation pathway can be activated downstream of NLRP3, potentially involving another caspase and/or another gasdermin. From our study it remains uncertain whether cytokines are secreted through GSDME pores in the setting of caspase-1 or GSDMD deficiency or are passively released when the cell membrane is grossly disrupted and LDH is released, as was recently proposed for in vitro GSDMD-mediated HMGB1 release 71 . Taken together, these results suggest that macrophages have more than one salvage mechanism to ensure that signals transmitted by inflammasome activators result in inflammation.…”

Section: Discussionmentioning

confidence: 84%

Activation of GSDME compensates for GSDMD deficiency in a mouse model of NLRP3 inflammasomopathy

Wang

Yang

Xiao

et al. 2021

Preprint

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The D301N NLRP3 mutation in mice (D303N in humans) causes severe multi-organ damage and early death driven by the constitutively activated NLRP3 (NLRP3ca) inflammasome. Triggered inflammasomes activate caspase-1 to process IL-1 family cytokines and gasdermin D (GSDMD), generating N-terminal fragments, which oligomerize within the plasma membrane to form pores, which cause inflammatory cell death (pyroptosis) and through which IL-1β and IL-18 are secreted. GSDMD activation is central to disease symptoms since spontaneous inflammation in Nlrp3ca;Gsdmd-/- mice is negligible. Unexpectedly, when Nlrp3ca;Gsdmd-/- mice were challenged with LPS or TNF-α, they secreted high amounts of IL-1β and IL-18, suggesting an alternative GSDMD-independent inflammatory pathway. Here we show that GSDMD deficient macrophages subjected to inflammatory stimuli activate caspase-8, -3 and GSDME-dependent cytokine release and pyroptosis. Caspase-8, -3 and GSDME also activated pyroptosis when NLRP3 was stimulated in caspase-1 deficient macrophages. Thus, a salvage caspase-8, -3-GSDME inflammatory pathway is activated following NLRP3 activation when the canonical NLRP3-caspase-1-GSDMD is blocked. Surprisingly, the active metabolite of the GSDMD-inhibitor disulfiram, inhibited not only GSDMD but also GSDME-mediated inflammation in vitro and suppressed severe inflammatory disease symptoms in Nlrp3ca mice, a model for severe neonatal multisystem inflammatory disease. Although disulfiram did not directly inhibit GSDME, it suppressed inflammasome activation in GSDMD-deficient cells. Thus, the combination of inflammatory signals and NLRP3ca overwhelmed the protection provided by GSDMD deficiency, rewiring signaling cascades through caspase-8, -3 and GSDME to propagate inflammation. This functional redundancy suggests that concomitant inhibition of GSDMD and GSDME may be necessary to suppress disease in inflammasomopathy patients.

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Indirect regulation of HMGB1 release by gasdermin D

Cited by 144 publications

References 60 publications

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

Necroptosis, pyroptosis and apoptosis: an intricate game of cell death

Activation of GSDME compensates for GSDMD deficiency in a mouse model of NLRP3 inflammasomopathy

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