Caspase-8 and FADD: Where Cell Death and Inflammation Collide

Amaral, Marcelo Pires; Bortoluci, Karina Ramalho

doi:10.1016/j.immuni.2020.05.008

Cited by 13 publications

(6 citation statements)

References 10 publications

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“…Post-mortem lung sections has revealed that pulmonary inflammatory responses may induce infiltration of inflammatory cells that trigger strong immune pathogenesis ( Li et al, 2020 ). Mechanisms of inflammatory response and cell death are strongly linked during SARS-CoV-2 infection ( Amaral and Bortoluci, 2020 ). The infection of lung cells activates caspase-8 to trigger cell death pathways, where apoptosis, pyroptosis, and necroptosis are involved.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials

et al. 2022

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Background: It is imperative to identify drugs that allow treating symptoms of severe COVID-19. Respiratory failure is the main cause of death in severe COVID-19 patients, and the host inflammatory response at the lungs remains poorly understood.Methods: Therefore, we retrieved data from post-mortem lungs from COVID-19 patients and performed in-depth in silico analyses of single-nucleus RNA sequencing data, inflammatory protein interactome network, and shortest pathways to physiological phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials.Results: Herein, we analyzed transcriptomics data of 719 inflammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 significantly expressed genes showed that the most relevant biological annotations were inflammatory response, innate immune response, cytokine production, interferon production, macrophage activation, blood coagulation, NLRP3 inflammasome complex, and the TLR, JAK-STAT, NF-κB, TNF, oncostatin M signaling pathways. Subsequently, we identified 34 essential inflammatory proteins with both high-confidence protein interactions and shortest pathways to inflammation, cell death, glycolysis, and angiogenesis.Conclusion: We propose three small molecules (baricitinib, eritoran, and montelukast) that can be considered for treating severe COVID-19 symptoms after being thoroughly evaluated in COVID-19 clinical trials.

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Section: Discussionmentioning

confidence: 99%

Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials

et al. 2022

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“…Although the conventional idea that inflammatory caspase activation would be protective by enhancing immunity against SARS-CoV-2 through the removal of infected cells and recruitment of monocytes to injury sites, concomitant pyroptosis exacerbating inflammation due to cellular release of DAMPs could lead to tissue death, organ failure, and septic shock (70,71). While caspase-8 is known predominately as a mediator of apoptosis, it is also a master regulator of pyroptosis and necroptosis (72) and is capable of processing pro-IL-1b and pro-IL-18 into their functional cytokine forms (73)(74)(75). Caspase-8 can regulate necroptosis, unregulated cell death, by preventing the phosphorylation of MLKL into its active form, phospho-MLKL, by inactivating RIPK1 and RIPK3 by proteolytic cleavage (76)(77)(78).…”

Section: Caspase-mediated Inflammation and Pyroptosismentioning

confidence: 99%

Emerging Insights on Caspases in COVID-19 Pathogenesis, Sequelae, and Directed Therapies

et al. 2022

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Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant global health emergency with new variants in some cases evading current therapies and approved vaccines. COVID-19 presents with a broad spectrum of acute and long-term manifestations. Severe COVID-19 is characterized by dysregulated cytokine release profile, dysfunctional immune responses, and hypercoagulation with a high risk of progression to multi-organ failure and death. Unraveling the fundamental immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and design of more effective therapeutic interventions for individuals at the highest risk of severe outcomes. Caspases are expressed in both immune and non-immune cells and mediate inflammation and cell death, including apoptosis and pyroptosis. Here we review accumulating evidence defining the importance of the expression and activity of caspase family members following SARS-CoV-2 infection and disease. Research suggests SARS-CoV-2 infection is linked to the function of multiple caspases, both mechanistically in vitro as well as in observational studies of individuals with severe COVID-19, which may further the impact on disease severity. We also highlight immunological mechanisms that occur in severe COVID-19 pathology upstream and downstream of activated caspase pathways, including innate recognition receptor signaling, inflammasomes, and other multiprotein complex assembly, inflammatory mediators IL-1β and IL-18, and apoptotic and pyroptotic cell death. Finally, we illuminate discriminate and indiscriminate caspase inhibitors that have been identified for clinical use that could emerge as potential therapeutic interventions that may benefit clinical efforts to prevent or ameliorate severe COVID-19.

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“…Caspase-8, which was previously viewed exclusively as an apoptotic caspase, has now emerged as a master regulator of the three major cell death pathways, including apoptosis, pyroptosis, and necroptosis. 7 Recently, it was reported that caspase-8 can induce the expression of pro-inflammatory cytokines and process pro-IL-1β and IL-18 in the same way as caspase-1, resulting in the release of bioactive cytokines, through either pyroptosis or necroptosis. 8 The role of caspase-8 in mediating inflammatory responses has been reported in the context of infection with fungal pathogens such as Candida albicans and Aspergillus fumigatus.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

Zhang

Guan

et al. 2020

Sig Transduct Target Ther

304

346

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.

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Caspase-8 and FADD: Where Cell Death and Inflammation Collide

Cited by 13 publications

References 10 publications

Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials

Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials

Emerging Insights on Caspases in COVID-19 Pathogenesis, Sequelae, and Directed Therapies

SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

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