Channelling inflammation: gasdermins in physiology and disease

Liu, Xing; Xia, Shiyu; Zhang, Zhibin; Wu, Hao; Lieberman, Judy

doi:10.1038/s41573-021-00154-z

Cited by 478 publications

(458 citation statements)

References 206 publications

(400 reference statements)

Supporting

Mentioning

447

Contrasting

Unclassified

Order By: Relevance

“…GSDMD is another attractive target as pore formation occurs downstream of all inflammasome sensors but upstream of IL-1β and DAMP release 166 . Two known small-molecule drugs have recently been described to inhibit GSDMD.…”

Section: Clinical Interventionsmentioning

confidence: 99%

Inflammasome activation at the crux of severe COVID-19

2021

Self Cite

View full text Add to dashboard Cite

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and pyroptosis, an inflammatory form of cell death. We further discuss potential mechanisms of inflammasome activation and clinical efforts currently under way to suppress inflammation to prevent or ameliorate severe COVID-19.

show abstract

Section: Clinical Interventionsmentioning

confidence: 99%

Inflammasome activation at the crux of severe COVID-19

2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Then, the activated caspases cleave GSDMD, contributing to the oligomerization of the N-terminal in membranes to form pores [ 16 , 17 , 18 , 19 , 20 ], leading to lytic cell death and the release of inflammatory cytokines such as IL-18, IL1β, and HMGB1 [ 21 ]. Later, it was discovered that the gasdermin family GSDMA/B/C/D/E could all be cleaved by activated caspases and granzyme proteases, and the N-terminal oligomerizes in membranes to form pores [ 22 ], leading to pyroptosis ( Figure 1 ).…”

Section: The Discovery Of Pyroptosismentioning

confidence: 99%

Pyroptosis in Cancer: Friend or Foe?

Guo

Zhang

2021

Cancers

View full text Add to dashboard Cite

Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in pyroptosis. Though all the gasdermin proteins have been studied in cancer, the role of pyroptosis in cancer remains mysterious, with conflicting findings. Numerous studies have shown that various stimuli, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and chemotherapeutic drugs, could trigger pyroptosis when the cells express GSDMs. However, it is not clear whether pyroptosis in cancer induced by chemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity. This review discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer, with an emphasis on tumor immunity.

show abstract

“…Junqueira et al, 7/26/21, page 3 cells (monocytes, macrophages, dendritic cells) are sentinels that sound the innate immune alarm by sensing invasive infection and danger to activate inflammasomes 8 . They are often the most important source of inflammatory cytokines during inflammation, and their activation is required to process and release IL-1 family cytokines, arguably the most potent inflammatory mediators in the body 9 .…”

mentioning

confidence: 99%

“…However other pathways, including NF-kB activation by Toll-like receptors or the TNF receptor superfamily and TH17 lymphocyte cytokines, can also cause severe inflammation. When inflammasomes sense danger or infection, they recruit the ASC adaptor and assemble into large supramolecular complexes that recruit and activate caspase-1, which in turn processes interleukin (IL)-1 family pro-cytokines and the pore-forming protein GSDMD that damages the cell membrane, leading to cell death and inflammatory cytokine release 8 . Cell membrane rupture during pyroptosis releases cytokines, chemokines and other alarmins that recruit and activate immune cells to sites of infection.…”

mentioning

confidence: 99%

“…Cell membrane rupture during pyroptosis releases cytokines, chemokines and other alarmins that recruit and activate immune cells to sites of infection. Release of large proteins such as the tetramer LDH (144 kDa), is a pathognomonic feature of pyroptosis and other forms of necrotic cell death 8 . Elevated LDH is one of the best correlates of severe COVID-19 disease 6 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

Junqueira

Crespo

Ranjbar

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in a minority of patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes and macrophages are sentinel immune cells in the blood and tissue, respectively, that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). We find that about 10% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on viral antibody opsonization and uptake of opsonized virus by the Fc receptor CD16. After uptake, SARS-CoV-2 begins to replicate in monocytes, as evidenced by detection of double-stranded RNA and subgenomic RNA and expression of a fluorescent reporter gene. However, infection is aborted, and infectious virus is not detected in infected monocyte supernatants or patient plasma. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of the NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial cells, from COVID-19 lung autopsy specimens showed evidence of inflammasome activation. These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to severe COVID-19 disease pathogenesis.

show abstract

Channelling inflammation: gasdermins in physiology and disease

Cited by 478 publications

References 206 publications

Inflammasome activation at the crux of severe COVID-19

Inflammasome activation at the crux of severe COVID-19

Pyroptosis in Cancer: Friend or Foe?

SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

Contact Info

Product

Resources

About