Alarmin cues and regulated cell death calibrate mucosal immunoglobulin A responses and virologic control after intranasal whole-virion inactivated influenza vaccination
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2026
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Abstract
How tissue damage cues and regulated cell death programs instruct antigen-specific mucosal IgA after vaccination remains incompletely defined. 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-33 release and a macrophage death-program switch that unmasks interleukin-1α. Immunization was accompanied by lung cell death, interleukin-33 release, and the induction of antigen-specific mucosal immunoglobulin A. In alveolar macrophages, vaccine uptake required phagocytosis and was associated with lysosomal destabilization and cathepsin B activity, which were linked to interleukin-1α 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 immunoglobulin A-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 interleukin-1α. Together, these data support a model in which alarmin cues and regulated cell death pathways in the lung modulate the magnitude of mucosal immunoglobulin A 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.
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| Authors | Eita Sasaki, Hideki Asanuma, Yoshimasa Takahashi, Hideki Hasegawa |
| Journal | international immunology |
| Year | 2026 |
| DOI |
10.1093/intimm/dxag023
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| URL | |
| Keywords | Keywords not found |
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