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Using a mouse model of intranasal whole-virion inactivated influenza vaccination, we identify two proximal inputs that shape antibody output and virologic control: epithelial necroptosis-associated interleukin (IL)-33 release and a macrophage death-program switch that unmasks IL-1\u03b1. Immunization was accompanied by lung cell death, IL-33 release, and the induction of antigen-specific mucosal IgA. In alveolar macrophages, vaccine uptake required phagocytosis and was associated with lysosomal destabilization and cathepsin B activity, which were linked to IL-1\u03b1 release under conditions that favored regulated necrotic cell death. Consistent with this, pharmacologic inhibition of caspases shifted the dominant death program in alveolar macrophages and was associated with enhanced B cell activation in the cervical lymph nodes and increased iIgA-producing cell-like populations. At the functional level, caspase inhibition augmented vaccine-elicited protection, including reduced lung viral titers and attenuated pathology after homologous challenge and improved control of a within-subtype drift influenza A virus challenge strain; these enhancements were partly dependent on IL-1\u03b1. Together, these data support a model in which alarmin cues and regulated cell death pathways in the lung modulate the magnitude of mucosal IgA responses and contribute to virologic control after intranasal whole-virion inactivated influenza vaccination. Limitations include reliance on pharmacologic pathway modulation and a mouse intranasal whole-virion inactivated influenza vaccine model; thus, mechanistic generalization beyond this context should be made cautiously.<\/jats:p>","DOI":"10.1093\/intimm\/dxag023","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T11:40:18Z","timestamp":1778326818000},"page":"626-644","source":"Crossref","is-referenced-by-count":0,"title":["Alarmin cues and regulated cell death calibrate mucosal immunoglobulin A responses and virologic control after intranasal whole-virion inactivated influenza vaccination"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3384-7414","authenticated-orcid":false,"given":"Eita","family":"Sasaki","sequence":"first","affiliation":[{"name":"Influenza Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security , 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011 ,","place":["Japan"]},{"name":"Research Center for Vaccine Development, National Institute of Infectious Diseases, Japan Institute for Health Security , 1-23-1 Toyama, Shinjuku, Tokyo 162-8640 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Asanuma","sequence":"additional","affiliation":[{"name":"Influenza Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security , 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimasa","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Research Center for Vaccine Development, National Institute of Infectious Diseases, Japan Institute for Health Security , 1-23-1 Toyama, Shinjuku, Tokyo 162-8640 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Influenza Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security , 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011 ,","place":["Japan"]},{"name":"Institute for Vaccine Research and Development, Hokkaido University , Sapporo 001-0021 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026100105520920100_dxag023-B1","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1111\/1348-0421.12775","article-title":"Human immune responses elicited by an intranasal inactivated H5 influenza vaccine","volume":"64","author":"Ainai","year":"2020","journal-title":"Microbiol Immunol"},{"key":"2026100105520920100_dxag023-B2","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.4049\/jimmunol.173.3.1978","article-title":"Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract","volume":"173","author":"Renegar","year":"2004","journal-title":"J. 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