{"doi":"10.64898/2026.06.19.733458","title":"Cytokines driven by caspase-1 and RIPK3 are antagonistic","abstract":"<jats:title>Summary</jats:title>\n                <jats:p>\n                  Pyroptosis, apoptosis, and necroptosis are thought to provide redundant protection against intracellular pathogens. We found that mice lacking inflammasomes, caspase-8, and MLKL were highly susceptible to infection by an environmental cytosol-invasive bacterium. Surprisingly, deletion of\n                  <jats:italic>Ripk3</jats:italic>\n                  completely restored resistance despite the continued absence of all three cell death pathways. The infection outcome was determined instead by the production of antagonistic cytokines arising from these pathways. Deletion of\n                  <jats:italic>Casp8</jats:italic>\n                  and\n                  <jats:italic>Mlkl</jats:italic>\n                  initiated an effector-triggered immunity-like response, in which RIPK3 induced type I interferons causing catastrophic susceptibility by impeding neutrophil responses. Opposing this, caspase-1-dependent IL-1β production counteracted these type I interferons and restored resistance. Thus, susceptibility arose not from failure of regulated cell death, but from the activation of RIPK3-driven type I interferons unopposed by caspase-1-driven IL-1β. Therefore, antagonistic cytokines embedded within cell death pathway signaling, distinct from cell death itself, can dictate the immune response to intracellular infection.\n                </jats:p>","journal":null,"year":null,"id":624081,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1613159,"name":"Jinyi (Sammy) Guo","orcid":null,"position":1,"is_corresponding":false},{"id":471260,"name":"Ying Wang","orcid":"0000-0001-6638-8026","position":2,"is_corresponding":false},{"id":702160,"name":"Carolyn A. Lacey","orcid":"0000-0003-3022-1712","position":3,"is_corresponding":false},{"id":244894,"name":"Yaxin Liu","orcid":"0000-0002-0981-5746","position":4,"is_corresponding":false},{"id":1613160,"name":"Jianxiang Peng","orcid":null,"position":5,"is_corresponding":false},{"id":1613161,"name":"Yu-Ming Li","orcid":null,"position":6,"is_corresponding":false},{"id":925670,"name":"Heather N. Larson","orcid":"0009-0007-2239-8274","position":7,"is_corresponding":false},{"id":1613163,"name":"Melanie N. Pratt","orcid":null,"position":8,"is_corresponding":false},{"id":225729,"name":"Bart Tummers","orcid":"0000-0001-7580-778X","position":9,"is_corresponding":false},{"id":1613164,"name":"Douglas R Green","orcid":null,"position":10,"is_corresponding":false},{"id":293211,"name":"Edward A. Miao","orcid":"0000-0001-7295-3490","position":11,"is_corresponding":false},{"id":517632,"name":"Lupeng Li","orcid":"0000-0003-3455-8179","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Cytokines driven by caspase-1 and RIPK3 are antagonistic","abstract":"<jats:title>Summary</jats:title>\n                <jats:p>\n                  Pyroptosis, apoptosis, and necroptosis are thought to provide redundant protection against intracellular pathogens. We found that mice lacking inflammasomes, caspase-8, and MLKL were highly susceptible to infection by an environmental cytosol-invasive bacterium. Surprisingly, deletion of\n                  <jats:italic>Ripk3</jats:italic>\n                  completely restored resistance despite the continued absence of all three cell death pathways. The infection outcome was determined instead by the production of antagonistic cytokines arising from these pathways. Deletion of\n                  <jats:italic>Casp8</jats:italic>\n                  and\n                  <jats:italic>Mlkl</jats:italic>\n                  initiated an effector-triggered immunity-like response, in which RIPK3 induced type I interferons causing catastrophic susceptibility by impeding neutrophil responses. Opposing this, caspase-1-dependent IL-1β production counteracted these type I interferons and restored resistance. Thus, susceptibility arose not from failure of regulated cell death, but from the activation of RIPK3-driven type I interferons unopposed by caspase-1-driven IL-1β. Therefore, antagonistic cytokines embedded within cell death pathway signaling, distinct from cell death itself, can dictate the immune response to intracellular infection.\n                </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"42368007","pmcid":null,"openalex_id":"https://openalex.org/W7165492821","authors":[],"funders":[{"funder_name":"","grant_id":"AI136920","title":null},{"funder_name":"","grant_id":"AI175078","title":null},{"funder_name":"","grant_id":"AI181815","title":null}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"https://www.biorxiv.org/about/FAQ#license","oa_locations":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13308195/","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13308195/","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.64898/2026.06.19.733458","host_type":"publisher"},{"url":"https://doi.org/10.64898/2026.06.19.733458","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/42368007","host_type":"repository"}],"fields_of_study":["Inflammasome and immune disorders","interferon and immune responses","Cell death mechanisms and regulation"],"mesh_terms":[],"keywords":["Necroptosis","Programmed cell death","Inflammasome","Intracellular","Immune system","Interferon","Intracellular parasite","Signal transduction","Cell"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T02:33:52.996928Z","pmid":null,"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":[]}