<scp>GSDMD</scp> drives canonical inflammasome‐induced neutrophil pyroptosis and is dispensable for <scp>NETosis</scp>

Chauhan, Dhruv; Demon, Dieter; Walle, Lieselotte Vande; Paerewijck, Oonagh; Zecchin, Annalisa; Bosseler, Leslie; Santoni, Karin; Planès, Rémi; Ribó, Sílvia; Fossoul, Amelie; Gonçalves, Amanda; Gorp, Hanne Van; Opdenbosch, Nina Van; Hauwermeiren, Filip Van; Meunier, Étienne; Wullaert, Andy; Lamkanfi, Mohamed

doi:10.15252/embr.202154277

Cited by 46 publications

(56 citation statements)

References 61 publications

(153 reference statements)

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“…Nonetheless, our study did not exclude other mechanisms that might also be involved in the GSDMD-mediated lung injury upon LPS challenge. Many studies have found that GSDMD is necessary for neutrophil IL-1β release [20,36], and in our study, we also found that IL-1β and IL-18 levels in the lungs of LPS-challenged mice were also reduced after neutrophil GSDMD-specific knockout. Thus, the secretion of IL-1β and IL-18 by GSDMD cleavage in neutrophils might also be a cause of ARDS.…”

Section: Discussionsupporting

confidence: 81%

GSDMD‐mediated NETosis promotes the development of acute respiratory distress syndrome

et al. 2022

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Gasdermin D (GSDMD) is a classical molecule involved in pyroptosis. It has been reported to be cleaved into N‐terminal fragments to form pores in the neutrophil membrane and promote the release of neutrophil extracellular traps (NETs). However, it remains unclear if GSDMD is involved in neutrophil regulation and NET release during ARDS. The role of neutrophil GSDMD in the development of ARDS was investigated in a murine model of ARDS induced by lipopolysaccharide (LPS) using the neutrophil specific GSDMD‐deficient mice. The neutrophil GSDMD cleavage and its relationship with NETosis were also explored in ARDS patients. The cleavage of GSDMD in neutrophils from ARDS patients and mice was upregulated. Inhibition of GSDMD by genetic knockout or inhibitors resulted in reduced production of NET both in vivo and in vitro, and attenuation of LPS‐induced lung injury. Moreover, in vitro experiments showed that the inhibition of GSDMD attenuated endothelial injury co‐cultured with neutrophils from ARDS patients, while extrinsic NETs reversed the protective effect of GSDMD inhibition. Collectively, our data suggest that the neutrophil GSDMD cleavage is crucial in NET release during ARDS. The NET release maintained by cleaved GSDMD in neutrophils may be a key event in the development of ARDS.

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Section: Discussionsupporting

confidence: 81%

GSDMD‐mediated NETosis promotes the development of acute respiratory distress syndrome

et al. 2022

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“…Recent functional studies have demonstrated that human and murine neutrophils express high levels of GSDMD 54,56,75,78,79,99–106 and GSDME 78,102 protein; analyses of the possible expression of the other GSDM proteins in neutrophils have not been reported. Although comprehensive transcriptomic profiling of GSDM family expression in neutrophils has not been reported, our RNA‐Seq analysis of FACS isolated (>99%) murine neutrophil populations revealed high gene expression of GSDME and GSDMD, but no other murine GSDM family members (E. Pearlman and G.R.…”

Section: Inflammasomes and Gasdermins As Critical Regulators Of Pyrop...mentioning

confidence: 99%

“…Notably, a very recent study by Chauhan et al 75 reported that ATP‐ or nigericin‐induced activation of NLRP3 inflammasomes in murine neutrophils resulted in a GSDMD‐dependent secretion of IL‐1β but also GSDMD‐dependent uptake of SytoxGreen (a DNA‐intercalating dye similar to propidium) indicative of accumulated N‐GSDMD pores in the plasma membrane. However, the number of SytoxGreen + neutrophils in the stimulated conditions was quite modest (~15% vs. 5–7% in unstimulated neutrophils) even after 100 minutes.…”

Section: Neutrophil Inflammasome Signaling Pathways That Facilitate R...mentioning

confidence: 99%

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

Dubyak

Miller

Pearlman

2023

Immunological Reviews

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Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins.It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

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“…Neutrophils are the first and most plentiful cells that permeate through the inflammatory region, where they can receive DAMPs ( 98 ) and then release many secretory vesicles containing proinflammatory factors and phagocytose pathogens to antagonize inflammation ( 99 ). Researchers have proven that neutrophils are an important source of IL-1β in both mice and human and that higher mRNA and protein levels of AIM2, ASC, and caspase-1 and AIM2 can induce GSDMD pyroptosis in neutrophils ( 85 , 86 ). AIM2-mediated secretion of IL-1β upregulates IL-17 release by T cells of a murine model of atherosclerosis, which then drives chemokines such as CXC motif chemokine ligand 1 (CXCL1) and CXCL2 to recruit more neutrophils during inflammation ( 87 ).…”

Section: Activation Of the Aim2 Inflammasome In Immune Cellsmentioning

confidence: 99%

AIM2 and Psoriasis

Zhang

Cheng

et al. 2023

Front. Immunol.

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Psoriasis is a chronic inflammatory skin disease occurring worldwide, with multiple systemic complications, which seriously affect the quality of life and physical and mental health of patients. The pathogenesis of psoriasis is related to the environment, genetics, epigenetics, and dysregulation of immune cells such as T cells, dendritic cells (DCs), and nonimmune cells such as keratinocytes. Absent in melanoma 2 (AIM2), a susceptibility gene locus for psoriasis, has been strongly linked to the genetic and epigenetic aspects of psoriasis and increased in expression in psoriatic keratinocytes. AIM2 was found to be activated in an inflammasome-dependent way to release IL-1β and IL-18 to mediate inflammation, and to participate in immune regulation in psoriasis, or in an inflammasome-independent way by regulating the function of regulatory T(Treg) cells or programming cell death in keratinocytes as well as controlling the proliferative state of different cells. AIM2 may also play a role in the recurrence of psoriasis by trained immunity. In this review, we will elaborate on the characteristics of AIM2 and how AIM2 mediates the development of psoriasis.

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GSDMD drives canonical inflammasome‐induced neutrophil pyroptosis and is dispensable for NETosis

Cited by 46 publications

References 61 publications

GSDMD‐mediated NETosis promotes the development of acute respiratory distress syndrome

GSDMD‐mediated NETosis promotes the development of acute respiratory distress syndrome

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

AIM2 and Psoriasis

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