{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T06:48:56Z","timestamp":1776235736147,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Caspase-1 is known to function intracellularly. However, whether caspase-1 can be released extracellularly and if so, the mechanisms of its release and action remain unknown. Here, we identify that cleaved caspase-1 (p20), which we named extracellular caspase-1 (eCasp-1), is released from immune cells in association with gasdermin D (GSDMD) pores formation. We identified significantly elevated eCasp-1 levels in the blood of critically ill surgical ICU patients, and in the blood and peritoneal fluid of gut ischemia-reperfusion (I\/R) injury mice.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , hypoxia-reoxygenation promoted GSDMD-dependent eCasp-1 release, and pharmacological inhibition of GSDMD reduced this release, supporting a contributing role of GSDMD-mediated membrane permeabilization in eCasp-1 release. Gut I\/R demonstrated robust GSDMD-dependent release of eCasp-1. Functionally, eCasp-1 engaged TLR4 on macrophages, eliciting robust inflammatory cytokine release and organ injury. Importantly, we developed a novel peptide, C16, designed to specifically inhibit the eCasp-1-TLR4 interaction. In gut I\/R, C16 administration exerted therapeutic benefits, markedly reducing systemic inflammation, attenuating acute lung injury (ALI), and significantly improving the survival. Our findings identify eCasp-1 as a new alarmin, that contributes to ALI through TLR4 signaling, with GSDMD-dependent processes contributing to its extracellular release. Targeting eCasp-1 with C16 offers a promising therapeutic strategy against ALI in acute inflammation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1811868","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T05:45:50Z","timestamp":1776231950000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular caspase-1: a critical inducer and a therapeutic target of lung injury in gut ischemia-reperfusion"],"prefix":"10.3389","volume":"17","author":[{"given":"Kouhei","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research","place":["Manhasset,\u00a0NY, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaifeng","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research","place":["Manhasset,\u00a0NY, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alok","family":"Jha","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research","place":["Manhasset,\u00a0NY, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Murao","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research","place":["Manhasset,\u00a0NY, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research","place":["Manhasset,\u00a0NY, United States"]},{"name":"Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell","place":["Manhasset, NY, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monowar","family":"Aziz","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research","place":["Manhasset,\u00a0NY, United States"]},{"name":"Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell","place":["Manhasset, NY, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.immuni.2020.06.007","article-title":"Caspase-1 engages full-length gasdermin d through two distinct interfaces that mediate caspase recruitment and substrate cleavage","volume":"53","author":"Liu","year":"2020","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15514","article-title":"Cleavage of gsdmd by inflammatory caspases determines pyroptotic cell death","volume":"526","author":"Shi","year":"2015","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-101220-030653","article-title":"Inflammatory caspases: toward a unified model for caspase activation by inflammasomes","volume":"40","author":"Ross","year":"2022","journal-title":"Annu Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/356768a0","article-title":"A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes","volume":"356","author":"Thornberry","year":"1992","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nature18629","article-title":"Inflammasome-activated gasdermin d causes pyroptosis by forming membrane pores","volume":"535","author":"Liu","year":"2016","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.139","article-title":"Gasdermin d is an executor of pyroptosis and required for interleukin-1\u03b2 secretion","volume":"25","author":"He","year":"2015","journal-title":"Cell Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41392-021-00507-5","article-title":"Pyroptosis: mechanisms and diseases","volume":"6","author":"Yu","year":"2021","journal-title":"Signal Transd Targ Ther"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03478-3","article-title":"Gasdermin d pore structure reveals preferential release of mature interleukin-1","volume":"593","author":"Xia","year":"2021","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41392-023-01688-x","article-title":"Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transd Targ Ther"},{"key":"B10","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/s42003-022-03887-8","article-title":"Integrated multi-omics reveal important roles of gut contents in intestinal ischemia-reperfusion induced injuries in rats","volume":"5","author":"Dai","year":"2022","journal-title":"Commun Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.100979","article-title":"Gut microbe-derived milnacipran enhances tolerance to gut ischemia\/reperfusion injury","volume":"4","author":"Deng","year":"2023","journal-title":"Cell Rep Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00840-2022","article-title":"Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischaemia\/reperfusion in mice","volume":"61","author":"Wang","year":"2023","journal-title":"Eur Respir J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(22)01485-4","article-title":"Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes","volume":"400","author":"Bos","year":"2022","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20205034","article-title":"Ischemia\/reperfusion injury revisited: an overview of the latest pharmacological strategies","volume":"20","author":"Soares","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s12967-023-04828-7","article-title":"Translational medicine for acute lung injury","volume":"22","author":"Zhang","year":"2024","journal-title":"J\u00a0Transl Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1397579","article-title":"Sex\u00a0differences in immune protection in mice conferred by heterologous vaccines for\u00a0pneumonic plague","volume":"15","author":"Davies","year":"2024","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1186\/s10020-025-01385-1","article-title":"The role of an anti-inflammatory molecule AIM\/CD5L in gut ischemia\/reperfusion injury of male mice","volume":"31","author":"Hollis","year":"2025","journal-title":"Mol Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s10020-024-00790-2","article-title":"Extracellular cirp induces cd4cd8\u03b1\u03b1 intraepithelial lymphocyte cytotoxicity in sepsis","volume":"30","author":"Akama","year":"2024","journal-title":"Mol Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2101004","article-title":"Active release of ecirp via\u00a0gasdermin d channels to induce inflammation in sepsis","volume":"208","author":"Tan","year":"2022","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0669-6","article-title":"FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin d pore formation","volume":"21","author":"Hu","year":"2020","journal-title":"Nat Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nmeth.3213","article-title":"The I-TASSER suite: protein structure and function prediction","volume":"12","author":"Yang","year":"2015","journal-title":"Nat Methods"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24728","article-title":"iATTRACT: simultaneous global and local\u00a0interface optimization for protein-protein docking refinement","volume":"83","author":"Schindler","year":"2015","journal-title":"Proteins"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl206","article-title":"GRAMM-X public web server for protein-protein docking","volume":"34","author":"Tovchigrechko","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.05.022","article-title":"Inference of macromolecular assemblies from crystalline state","volume":"372","author":"Krissinel","year":"2007","journal-title":"J Mol Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1097-0282(199603)38:3<305::aid-bip4>3.0.co;2-y","article-title":"Reduced surface: an efficient way to compute molecular surfaces","volume":"38","author":"Sanner","year":"1996","journal-title":"Biopolymers"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1597887","article-title":"A novel molecule targeting neutrophil-mediated B-1a cell trogocytosis attenuates sepsis-induced acute lung injury","volume":"16","author":"Akama","year":"2025","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1165\/rcmb.2021-0531st","article-title":"Update on the features and measurements of experimental acute lung injury in animals: an official American Thoracic Society workshop report","volume":"66","author":"Kulkarni","year":"2022","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-081022-021207","article-title":"Structural mechanisms of nlrp3 inflammasome assembly and activation","volume":"41","author":"Fu","year":"2023","journal-title":"Annu Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202502297","article-title":"Critical role of il1r2-eno1 interaction in inhibiting glycolysis-mediated pyroptosis for protection against lethal sepsis","volume":"12","author":"Tan","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1186\/s13054-020-02917-3","article-title":"Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study","volume":"24","author":"Stortz","year":"2020","journal-title":"Crit Care"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-023-07295-2","article-title":"ICU-acquired infections in immunocompromised patients","volume":"50","author":"Kreitmann","year":"2024","journal-title":"Intensive Care Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1097\/shk.0000000000002467","article-title":"A novel opsonic extracellular cirp inhibitor mop3 alleviates gut ischemia\/reperfusion injury","volume":"63","author":"Hollis","year":"2025","journal-title":"Shock"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12987","article-title":"Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia\/reperfusion injury","volume":"21","author":"Wen","year":"2017","journal-title":"J Cell Mol Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01192-4","article-title":"Caspase-11 interaction with nlrp3 potentiates the noncanonical activation of the nlrp3 inflammasome","volume":"23","author":"Moretti","year":"2022","journal-title":"Nat Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/srep45126","article-title":"Differential roles of caspase-1 and caspase-11 in infection and inflammation","volume":"7","author":"Man","year":"2017","journal-title":"Sci Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature18590","article-title":"Pore-forming activity and structural autoinhibition of the gasdermin family","volume":"535","author":"Ding","year":"2016","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142203","article-title":"Monocyte caspase-1 is released in a stable, active high molecular weight complex distinct from the unstable cell lysate-activated caspase-1","volume":"10","author":"Shamaa","year":"2015","journal-title":"PloS One"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20172222","article-title":"Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity","volume":"215","author":"Boucher","year":"2018","journal-title":"J Exp Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m111.225862","article-title":"Caspase-1 promiscuity is counterbalanced by rapid inactivation of processed enzyme","volume":"286","author":"Walsh","year":"2011","journal-title":"J Biol Chem"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.03.002","article-title":"DAMPs and DAMP-sensing receptors in inflammation and diseases","volume":"57","author":"Ma","year":"2024","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","first-page":"19417","DOI":"10.1038\/s41598-023-46756-y","article-title":"High-throughput analysis system of interaction kinetics for data-driven antibody design","volume":"13","author":"Matsunaga","year":"2023","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","first-page":"5359","DOI":"10.1038\/s41467-022-32796-x","article-title":"Improved immunoassay sensitivity and specificity using single-molecule colocalization","volume":"13","author":"Hariri","year":"2022","journal-title":"Nat Commun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2013.97","article-title":"Recognition of lipopolysaccharide pattern by tlr4 complexes","volume":"45","author":"Park","year":"2013","journal-title":"Exp Mol Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1172\/jci26252","article-title":"Caspases: pharmacological manipulation of cell death","volume":"115","author":"Lavrik","year":"2005","journal-title":"J Clin Invest"},{"key":"B46","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s10020-018-0023-8","article-title":"Exploring the biological functional mechanism of the HMGB1\/TLR4\/MD-2 complex by surface plasmon resonance","volume":"24","author":"He","year":"2018","journal-title":"Mol Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.2194","article-title":"Effect of eritoran, an antagonist of md2-tlr4, on mortality in patients with severe sepsis: the ACCESS randomized trial","volume":"309","author":"Opal","year":"2013","journal-title":"JAMA"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/cells13141172","article-title":"Evolving paradigms in sepsis management: a narrative review","volume":"13","author":"Kim","year":"2024","journal-title":"Cells"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1159\/000336713","article-title":"Lipopolysaccharide neutralization by antimicrobial peptides: a gambit in the innate host defense strategy","volume":"4","author":"Pulido","year":"2012","journal-title":"J Innate Immun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1811868\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T05:45:51Z","timestamp":1776231951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1811868\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2026.1811868"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1811868","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]},"article-number":"1811868"}}