{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:48:08Z","timestamp":1789390088424,"version":"build-2803163510"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alveolar macrophages (AMs) play a crucial role in protecting the lungs from pathogens by inducing immunogenic cell death (ICD). However, the type of cell death that effectively induces protective immunity remains to be fully understood. In our investigation of the mechanisms regulating AM activation and lung immune responses, we found that AMs are highly susceptible to necroptosis, a form of ICD. Treatment with pan-caspase inhibitors, such as emricasan or benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVAD-fmk), directly induced cell death in AMs, resulting in the release of interleukin (IL)-1\u03b1 in the lungs. This phenomenon was not observed in mouse lung fibroblasts or bone marrow-derived macrophages, indicating a cell type-specific sensitivity. The process was mediated by receptor-interacting protein kinase (RIPK)1 and RIPK3, and notably occurred without any additional necroptosis triggers such as tumor necrosis factor (TNF) or second mitochondria-derived activator of caspase (SMAC) mimetics. Moreover, activation of the RIPK1\u2013RIPK3 signaling pathway not only triggered necroptosis but also promoted IL-1\u03b1 production and release. These responses were absent in AMs lacking functional RIPK1 kinase activity or deficient in RIPK3. Importantly, RIPK1\/RIPK3-mediated cell death and IL-1\u03b1 release were sufficient to trigger lung immune responses, as shown by increased antigen-specific IgG and IgA production, which was significantly decreased in mice deficient in necroptosis or lacking the IL-1 receptor. Taken together, these findings demonstrate that the pan-caspase inhibitor emricasan induces necroptotic cell death in AMs and may act as a promising AM-targeted adjuvant to enhance lung-specific acquired immunity.<\/jats:p>","DOI":"10.1038\/s41419-025-08372-8","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T20:23:14Z","timestamp":1766434994000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Resident alveolar macrophages are highly susceptible to the induction of RIPK1\/RIPK3-mediated necroptosis which promote efficient pulmonary immune response"],"prefix":"10.1038","volume":"16","author":[{"given":"Takumi","family":"Adachi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazufumi","family":"Matsushita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koubun","family":"Yasuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakiyo","family":"Nakahira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Imasaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5888-5054","authenticated-orcid":false,"given":"Michihiko","family":"Sugimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0983-7462","authenticated-orcid":false,"given":"Zhuohao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouji","family":"Kobiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6728-3872","authenticated-orcid":false,"given":"Ken J.","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Yoshioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Ohmuraya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3808-1630","authenticated-orcid":false,"given":"Yoshitaka","family":"Shirasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-2190","authenticated-orcid":false,"given":"Etsushi","family":"Kuroda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"8372_CR1","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nri3600","volume":"14","author":"T Hussell","year":"2014","unstructured":"Hussell T, Bell TJ. Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol. 2014;14:81\u201393.","journal-title":"Nat Rev Immunol"},{"key":"8372_CR2","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1172\/JCI124615","volume":"129","author":"S Watanabe","year":"2019","unstructured":"Watanabe S, Alexander M, Misharin AV, Budinger GRS. The role of macrophages in the resolution of inflammation. J Clin Invest. 2019;129:2619\u201328.","journal-title":"J Clin Invest"},{"key":"8372_CR3","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1016\/j.immuni.2016.11.010","volume":"45","author":"E Kuroda","year":"2016","unstructured":"Kuroda E, Ozasa K, Temizoz B, Ohata K, Koo C, Kanuma T, et al. Inhaled fine particles induce alveolar macrophage death and interleukin-1 alpha release to promote inducible bronchus-associated lymphoid tissue formation. Immunity. 2016;45:1299\u2013310.","journal-title":"Immunity"},{"key":"8372_CR4","doi-asserted-by":"publisher","first-page":"e134356.","DOI":"10.1172\/jci.insight.134356","volume":"5","author":"MK Collins","year":"2020","unstructured":"Collins MK, Shotland AM, Wade MF, Atif SM, Richards DK, Torres-Llompart M. et al. A role for TNF-\u03b1 in alveolar macrophage damage-associated molecular pattern release. JCI Insight. 2020;5:e134356.","journal-title":"JCI Insight"},{"key":"8372_CR5","doi-asserted-by":"publisher","first-page":"12162","DOI":"10.1073\/pnas.211423598","volume":"98","author":"JM Trevejo","year":"2001","unstructured":"Trevejo JM, Marino MW, Philpott N, Josien R, Richards EC, Elkon KB, et al. TNF-alpha -dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection. Proc Natl Acad Sci USA. 2001;98:12162\u20137.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8372_CR6","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41590-022-01132-2","volume":"23","author":"G Kroemer","year":"2022","unstructured":"Kroemer G, Galassi C, Zitvogel L, Galluzzi L. Immunogenic cell stress and death. Nat Immunol. 2022;23:487\u2013500.","journal-title":"Nat Immunol"},{"key":"8372_CR7","doi-asserted-by":"publisher","first-page":"2529","DOI":"10.15252\/embj.201796476","volume":"36","author":"J Maelfait","year":"2017","unstructured":"Maelfait J, Liverpool L, Bridgeman A, Ragan KB, Upton JW, Rehwinkel J. Sensing of viral and endogenous RNA by ZBP1\/DAI induces necroptosis. EMBO J. 2017;36:2529\u201343.","journal-title":"EMBO J"},{"key":"8372_CR8","doi-asserted-by":"publisher","first-page":"20054","DOI":"10.1073\/pnas.1116302108","volume":"108","author":"S He","year":"2011","unstructured":"He S, Liang Y, Shao F, Wang X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc Natl Acad Sci USA. 2011;108:20054\u20139.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8372_CR9","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1084\/jem.187.9.1477","volume":"187","author":"D Vercammen","year":"1998","unstructured":"Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med. 1998;187:1477\u201385.","journal-title":"J Exp Med"},{"key":"8372_CR10","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/82732","volume":"1","author":"N Holler","year":"2000","unstructured":"Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1:489\u201395.","journal-title":"Nat Immunol"},{"key":"8372_CR11","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.cell.2009.05.021","volume":"137","author":"S He","year":"2009","unstructured":"He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137:1100\u201311.","journal-title":"Cell"},{"key":"8372_CR12","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.cell.2011.11.031","volume":"148","author":"L Sun","year":"2012","unstructured":"Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213\u201327.","journal-title":"Cell"},{"key":"8372_CR13","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.immuni.2013.02.003","volume":"38","author":"A Kaczmarek","year":"2013","unstructured":"Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013;38:209\u201323.","journal-title":"Immunity"},{"key":"8372_CR14","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/S1074-7613(00)80609-3","volume":"9","author":"EE Varfolomeev","year":"1998","unstructured":"Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas\/Apo1, and DR3 and is lethal prenatally. Immunity. 1998;9:267\u201376.","journal-title":"Immunity"},{"key":"8372_CR15","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1101\/gad.13.19.2514","volume":"13","author":"Y Lin","year":"1999","unstructured":"Lin Y, Devin A, Rodriguez Y, Liu ZG. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 1999;13:2514\u201326.","journal-title":"Genes Dev"},{"key":"8372_CR16","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1042\/BJ20101738","volume":"433","author":"C Pop","year":"2011","unstructured":"Pop C, Oberst A, Drag M, Van Raam BJ, Riedl SJ, Green DR, et al. FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem J. 2011;433:447\u201357.","journal-title":"Biochem J"},{"key":"8372_CR17","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/s41586-019-1548-x","volume":"574","author":"K Newton","year":"2019","unstructured":"Newton K, Wickliffe KE, Dugger DL, Maltzman A, Roose-Girma M, Dohse M, et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019;574:428\u201331.","journal-title":"Nature"},{"key":"8372_CR18","doi-asserted-by":"publisher","first-page":"2471","DOI":"10.1002\/1521-4141(200209)32:9<2471::AID-IMMU2471>3.0.CO;2-E","volume":"32","author":"C Scheller","year":"2002","unstructured":"Scheller C, Sopper S, Ehrhardt C, Flory E, Chen P, Koutsilieri E, et al. Caspase inhibitors induce a switch from apoptotic to proinflammatory signaling in CD95-stimulated T lymphocytes. Eur J Immunol. 2002;32:2471\u201380.","journal-title":"Eur J Immunol"},{"key":"8372_CR19","doi-asserted-by":"publisher","first-page":"eabd2223","DOI":"10.1126\/scitranslmed.abd2223","volume":"13","author":"D Sterlin","year":"2021","unstructured":"Sterlin D, Mathian A, Miyara M, Mohr A, Anna F, Cla\u00ebr L. et al. IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med. 2021;13:eabd2223","journal-title":"Sci Transl Med"},{"key":"8372_CR20","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1002\/eji.1830140414","volume":"14","author":"FY Liew","year":"1984","unstructured":"Liew FY, Russell SM, Appleyard G, Brand CM, Beale J. Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity. Eur J Immunol. 1984;14:350\u20136.","journal-title":"Eur J Immunol"},{"key":"8372_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/srep29165","volume":"6","author":"M Hayashi","year":"2016","unstructured":"Hayashi M, Aoshi T, Ozasa K, Kusakabe T, Momota M, Haseda Y, et al. RNA is an adjuvanticity mediator for the lipid-based mucosal adjuvant, endocine. Sci Rep. 2016;6:29165.","journal-title":"Sci Rep"},{"key":"8372_CR22","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.4049\/jimmunol.1400590","volume":"193","author":"A Polykratis","year":"2014","unstructured":"Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van TM, et al. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol. 2014;193:1539\u201343.","journal-title":"J Immunol"},{"key":"8372_CR23","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1093\/bioinformatics\/btu743","volume":"31","author":"Y Naito","year":"2015","unstructured":"Naito Y, Hino K, Bono H, Ui-Tei K. CRISPRdirect: software for designing CRISPR\/Cas guide RNA with reduced off-target sites. Bioinformatics. 2015;31:1120\u20133.","journal-title":"Bioinformatics"},{"key":"8372_CR24","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nbt.3437","volume":"34","author":"JG Doench","year":"2016","unstructured":"Doench JG, Fusi N, Sullender M, Hegde M, Vaimberg EW, Donovan KF, et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat Biotechnol. 2016;34:184\u201391.","journal-title":"Nat Biotechnol"},{"key":"8372_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07901-8","volume":"9","author":"KR Sanson","year":"2018","unstructured":"Sanson KR, Hanna RE, Hegde M, Donovan KF, Strand C, Sullender ME, et al. Optimized libraries for CRISPR-Cas9 genetic screens with multiple modalities. Nat Commun. 2018;9:5416.","journal-title":"Nat Commun"},{"key":"8372_CR26","doi-asserted-by":"publisher","first-page":"5791","DOI":"10.4049\/jimmunol.1401768","volume":"193","author":"K Matsushita","year":"2014","unstructured":"Matsushita K, Yoshimoto T. B cell-intrinsic MyD88 signaling is essential for IgE responses in lungs exposed to pollen allergens. J Immunol. 2014;193:5791\u2013800.","journal-title":"J Immunol"},{"key":"8372_CR27","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41556-019-0324-3","volume":"21","author":"A Polykratis","year":"2019","unstructured":"Polykratis A, Martens A, Eren RO, Shirasaki Y, Yamagishi M, Yamaguchi Y, et al. A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain. Nat Cell Biol. 2019;21:731\u201342.","journal-title":"Nat Cell Biol"},{"key":"8372_CR28","doi-asserted-by":"publisher","first-page":"e0184752","DOI":"10.1371\/journal.pone.0184752","volume":"12","author":"WK Saeed","year":"2017","unstructured":"Saeed WK, Jun DW, Jang K, Chae YJ, Lee JS, Kang HT. Does necroptosis have a crucial role in hepatic ischemia-reperfusion injury? PLoS ONE. 2017;12:e0184752.","journal-title":"PLoS ONE"},{"key":"8372_CR29","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/s41392-023-01557-7","volume":"8","author":"T Zhao","year":"2023","unstructured":"Zhao T, Cai Y, Jiang Y, He X, Wei Y, Yu Y, et al. Vaccine adjuvants: mechanisms and platforms. Signal Transduct Target Ther. 2023;8:283.","journal-title":"Signal Transduct Target Ther"},{"key":"8372_CR30","doi-asserted-by":"publisher","first-page":"D545","DOI":"10.1093\/nar\/gkaa970","volume":"49","author":"M Kanehisa","year":"2021","unstructured":"Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2021;49:D545\u2013D51.","journal-title":"Nucleic Acids Res"},{"key":"8372_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/srep04736","volume":"4","author":"Y Shirasaki","year":"2014","unstructured":"Shirasaki Y, Yamagishi M, Suzuki N, Izawa K, Nakahara A, Mizuno J, et al. Real-time single-cell imaging of protein secretion. Sci Rep. 2014;4:4736.","journal-title":"Sci Rep"},{"key":"8372_CR32","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41422-019-0164-5","volume":"29","author":"D Tang","year":"2019","unstructured":"Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29:347\u201364.","journal-title":"Cell Res"},{"key":"8372_CR33","doi-asserted-by":"publisher","first-page":"2003764.","DOI":"10.1183\/13993003.03764-2020","volume":"57","author":"LD Santos","year":"2021","unstructured":"Santos LD, Antunes KH, Muraro SP, de Souza GF, da Silva AG, Felipe JS. et al. TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection. Eur Respir J. 2021;57:2003764.","journal-title":"Eur Respir J"},{"key":"8372_CR34","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1038\/cdd.2017.19","volume":"24","author":"S Solier","year":"2017","unstructured":"Solier S, Fontenay M, Vainchenker W, Droin N, Solary E. Non-apoptotic functions of caspases in myeloid cell differentiation. Cell Death Differ. 2017;24:1337\u201347.","journal-title":"Cell Death Differ"},{"key":"8372_CR35","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41418-018-0172-x","volume":"26","author":"H Nailwal","year":"2019","unstructured":"Nailwal H, Chan FK. Necroptosis in anti-viral inflammation. Cell Death Differ. 2019;26:4\u201313.","journal-title":"Cell Death Differ"},{"key":"8372_CR36","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/j.cell.2020.02.050","volume":"180","author":"T Zhang","year":"2020","unstructured":"Zhang T, Yin C, Boyd DF, Quarato G, Ingram JP, Shubina M, et al. Influenza virus Z-RNAs induce ZBP1-mediated necroptosis. Cell. 2020;180:1115\u201329.e13.","journal-title":"Cell"},{"key":"8372_CR37","doi-asserted-by":"publisher","first-page":"aag2045.","DOI":"10.1126\/sciimmunol.aag2045","volume":"1","author":"T Kuriakose","year":"2016","unstructured":"Kuriakose T, Man SM, Malireddi RK, Karki R, Kesavardhana S, Place DE. et al. ZBP1\/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci Immunol. 2016;1:aag2045.","journal-title":"Sci Immunol"},{"key":"8372_CR38","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2008.03.036","volume":"133","author":"L Wang","year":"2008","unstructured":"Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 2008;133:693\u2013703.","journal-title":"Cell"},{"key":"8372_CR39","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/s41586-019-1770-6","volume":"575","author":"M Fritsch","year":"2019","unstructured":"Fritsch M, G\u00fcnther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 2019;575:683\u20137.","journal-title":"Nature"},{"key":"8372_CR40","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1084\/jem.20071632","volume":"205","author":"J Maelfait","year":"2008","unstructured":"Maelfait J, Vercammen E, Janssens S, Schotte P, Haegman M, Magez S, et al. Stimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8. J Exp Med. 2008;205:1967\u201373.","journal-title":"J Exp Med"},{"key":"8372_CR41","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.4049\/jimmunol.173.5.2976","volume":"173","author":"TB Kang","year":"2004","unstructured":"Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, et al. Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol. 2004;173:2976\u201384.","journal-title":"J Immunol"},{"key":"8372_CR42","doi-asserted-by":"publisher","first-page":"17779","DOI":"10.1074\/jbc.M600537200","volume":"281","author":"S Cathelin","year":"2006","unstructured":"Cathelin S, R\u00e9b\u00e9 C, Haddaoui L, Simioni N, Verdier F, Fontenay M, et al. Identification of proteins cleaved downstream of caspase activation in monocytes undergoing macrophage differentiation. J Biol Chem. 2006;281:17779\u201388.","journal-title":"J Biol Chem"},{"key":"8372_CR43","doi-asserted-by":"publisher","first-page":"4446","DOI":"10.1182\/blood-2002-06-1778","volume":"100","author":"O Sordet","year":"2002","unstructured":"Sordet O, R\u00e9b\u00e9 C, Plenchette S, Zermati Y, Hermine O, Vainchenker W, et al. Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood. 2002;100:4446\u201353.","journal-title":"Blood"},{"key":"8372_CR44","doi-asserted-by":"publisher","first-page":"12703","DOI":"10.1128\/JVI.01182-10","volume":"84","author":"H Kayamuro","year":"2010","unstructured":"Kayamuro H, Yoshioka Y, Abe Y, Arita S, Katayama K, Nomura T, et al. Interleukin-1 family cytokines as mucosal vaccine adjuvants for induction of protective immunity against influenza virus. J Virol. 2010;84:12703\u201312.","journal-title":"J Virol"},{"key":"8372_CR45","doi-asserted-by":"publisher","first-page":"6141","DOI":"10.4049\/jimmunol.162.10.6141","volume":"162","author":"HF Staats","year":"1999","unstructured":"Staats HF, Ennis FA. IL-1 is an effective adjuvant for mucosal and systemic immune responses when coadministered with protein immunogens. J Immunol. 1999;162:6141\u20137.","journal-title":"J Immunol"},{"key":"8372_CR46","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/S2468-1253(22)00005-X","volume":"7","author":"JL Alexander","year":"2022","unstructured":"Alexander JL, Kennedy NA, Ibraheim H, Anandabaskaran S, Saifuddin A, Castro Seoane R, et al. COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study. Lancet Gastroenterol Hepatol. 2022;7:342\u201352.","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"8372_CR47","doi-asserted-by":"publisher","first-page":"rkad065","DOI":"10.1093\/rap\/rkad065","volume":"7","author":"A Sch\u00e4fer","year":"2023","unstructured":"Sch\u00e4fer A, Kovacs MS, Eder A, Nigg A, Feuchtenberger M. TNF inhibitors significantly attenuate the humoral immune response to COVID-19 vaccination in patients with rheumatoid arthritis. Rheumatol Adv Pract. 2023;7:rkad065.","journal-title":"Rheumatol Adv Pract"},{"key":"8372_CR48","doi-asserted-by":"publisher","first-page":"5869","DOI":"10.1016\/j.biomaterials.2009.07.009","volume":"30","author":"H Kayamuro","year":"2009","unstructured":"Kayamuro H, Abe Y, Yoshioka Y, Katayama K, Nomura T, Yoshida T, et al. The use of a mutant TNF-alpha as a vaccine adjuvant for the induction of mucosal immune responses. Biomaterials. 2009;30:5869\u201376.","journal-title":"Biomaterials"},{"key":"8372_CR49","doi-asserted-by":"publisher","first-page":"339ra69","DOI":"10.1126\/scitranslmed.aad3099","volume":"8","author":"G Brumatti","year":"2016","unstructured":"Brumatti G, Ma C, Lalaoui N, Nguyen NY, Navarro M, Tanzer MC, et al. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci Transl Med. 2016;8:339ra69.","journal-title":"Sci Transl Med"},{"key":"8372_CR50","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1016\/j.cgh.2018.06.012","volume":"17","author":"CT Frenette","year":"2019","unstructured":"Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, et al. Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol. 2019;17:774\u201383.e4.","journal-title":"Clin Gastroenterol Hepatol"},{"key":"8372_CR51","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1111\/apt.15030","volume":"49","author":"M Shiffman","year":"2019","unstructured":"Shiffman M, Freilich B, Vuppalanchi R, Watt K, Chan JL, Spada A, et al. Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3\/7 activation in subjects with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2019;49:64\u201373.","journal-title":"Aliment Pharmacol Ther"},{"key":"8372_CR52","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.jceh.2017.11.006","volume":"8","author":"G Mehta","year":"2018","unstructured":"Mehta G, Rousell S, Burgess G, Morris M, Wright G, McPherson S, et al. A placebo-controlled, multicenter, double-blind, phase 2 randomized trial of the Pan-caspase inhibitor emricasan in patients with acutely decompensated cirrhosis. J Clin Exp Hepatol. 2018;8:224\u201334.","journal-title":"J Clin Exp Hepatol"},{"key":"8372_CR53","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1016\/j.jhep.2019.11.024","volume":"72","author":"SA Harrison","year":"2020","unstructured":"Harrison SA, Goodman Z, Jabbar A, Vemulapalli R, Younes ZH, Freilich B, et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol. 2020;72:816\u201327.","journal-title":"J Hepatol"},{"key":"8372_CR54","doi-asserted-by":"publisher","first-page":"8","DOI":"10.7883\/yoken.63.8","volume":"63","author":"S Tamura","year":"2010","unstructured":"Tamura S, Hasegawa H, Kurata T. Estimation of the effective doses of nasal-inactivated influenza vaccine in humans from mouse-model experiments. Jpn J Infect Dis. 2010;63:8\u201315.","journal-title":"Jpn J Infect Dis"},{"key":"8372_CR55","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.jaci.2017.12.971","volume":"141","author":"MM McNeil","year":"2018","unstructured":"McNeil MM, DeStefano F. Vaccine-associated hypersensitivity. J Allergy Clin Immunol. 2018;141:463\u201372.","journal-title":"J Allergy Clin Immunol"},{"key":"8372_CR56","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-018-2486-6","volume":"19","author":"SX Ge","year":"2018","unstructured":"Ge SX, Son EW, Yao R. iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data. BMC Bioinformatics. 2018;19:534.","journal-title":"BMC Bioinformatics"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08372-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08372-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08372-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T21:03:04Z","timestamp":1767042184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08372-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,22]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8372"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08372-8","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,22]]},"assertion":[{"value":"14 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Yasuo Yoshioka was employed by the Research Foundation for Microbial Diseases at The University of Osaka.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were performed according to the Guidelines for the Care and Use of Animals approved by Hyogo Medical University. (Approval numbers 22-035AG and 23-018AGP).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"919"}}