{"doi":"10.4049/jimmunol.2100757","title":"Cutting Edge: Caspase-8 Is a Linchpin in Caspase-3 and Gasdermin D Activation to Control Cell Death, Cytokine Release, and Host Defense during Influenza A Virus Infection","abstract":"Abstract Programmed cell death (PCD) is essential for the innate immune response, which serves as the first line of defense against pathogens. Caspases regulate PCD, immune responses, and homeostasis. Caspase-8 specifically plays multifaceted roles in PCD pathways including pyroptosis, apoptosis, and necroptosis. However, because caspase-8–deficient mice are embryonically lethal, little is known about how caspase-8 coordinates different PCD pathways under physiological conditions. Here, we report an anti-inflammatory role of caspase-8 during influenza A virus infection. We generated viable mice carrying an uncleavable version of caspase-8 (Casp8DA/DA). We demonstrated that caspase-8 autoprocessing was responsible for activating caspase-3, thereby suppressing gasdermin D–mediated pyroptosis and inflammatory cytokine release. We also found that apoptotic and pyroptotic pathways were activated at the same time during influenza A virus infection, which enabled the cell-intrinsic anti-inflammatory function of the caspase-8–caspase-3 axis. Our findings provide new insight into the immunological consequences of caspase-8–coordinated PCD cross-talk under physiological conditions.","journal":"The Journal of Immunology","year":2021,"id":159716,"datarank":0.5570358100056463,"base_score":3.713572066704308,"endowment":3.713572066704308,"self_citation_contribution":0.5570358100056463,"citation_network_contribution":0.0,"self_endowment_contribution":0.5570358100056463,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":105431,"name":"Rajendra Karki","orcid":"0000-0003-4436-9128","position":1,"is_corresponding":false},{"id":671097,"name":"Min Zheng","orcid":"0000-0002-0343-3368","position":2,"is_corresponding":false},{"id":244989,"name":"Balabhaskararao Kancharana","orcid":"0000-0002-1362-4942","position":3,"is_corresponding":false},{"id":241089,"name":"SangJoon Lee","orcid":"0000-0001-7500-782X","position":4,"is_corresponding":false},{"id":107636,"name":"Sannula Kesavardhana","orcid":"0000-0002-9536-8830","position":5,"is_corresponding":false},{"id":569926,"name":"Baranda S. Hansen","orcid":"0000-0003-2299-650X","position":6,"is_corresponding":false},{"id":250571,"name":"Shondra M. Pruett‐Miller","orcid":"0000-0002-3793-585X","position":7,"is_corresponding":false},{"id":105446,"name":"Thirumala‐Devi Kanneganti","orcid":"0000-0002-6395-6443","position":8,"is_corresponding":false},{"id":575952,"name":"Yaqiu Wang","orcid":"0000-0002-6827-5495","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:44:39.550981Z","pmid":"34663620","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}