Nasal alum-adjuvanted vaccine promotes IL-33 release from alveolar epithelial cells that elicits IgA production via type 2 immune responses

• Published in: PLoS pathogens Vol. 17; no. 8; p. e1009890
• Main Authors: Sasaki, Eita, Asanuma, Hideki, Momose, Haruka, Furuhata, Keiko, Mizukami, Takuo, Hamaguchi, Isao
• Format: Journal Article
• Language: English
• Published: San Francisco, CA USA Public Library of Science 30.08.2021; Public Library of Science (PLoS)
• Subjects: Biology and Life Sciences; Genetic aspects; Health aspects; Immune response; Immunoglobulins; Interleukins; Medicine and Health Sciences; Patient outcomes; People and Places; Research and Analysis Methods; Vaccination; Japan
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009890

Aluminum hydroxide salts (alum) have been added to inactivated vaccines as safe and effective adjuvants to increase the effectiveness of vaccination. However, the exact cell types and immunological factors that initiate mucosal immune responses to alum adjuvants are unclear. In this study, the mechanism of action of alum adjuvant in nasal vaccination was investigated. Alum has been shown to act as a powerful and unique adjuvant when added to a nasal influenza split vaccine in mice. Alum is cytotoxic in the alveoli and stimulates the release of damage-associated molecular patterns, such as dsDNA, interleukin (IL)-1α, and IL-33. We found that Ag-specific IgA antibody (Ab) production was markedly reduced in IL-33-deficient mice. However, no decrease was observed in Ag-specific IgA Ab production with DNase I treatment, and no decrease was observed in IL-1α/β or IL-6 production in IL-33-deficient mice. From the experimental results of primary cultured cells and immunofluorescence staining, although IL-1α was secreted by alveolar macrophage necroptosis, IL-33 release was observed in alveolar epithelial cell necroptosis but not in alveolar macrophages. Alum- or IL-33-dependent Ag uptake enhancement and elevation of OX40L expression were not observed. By stimulating the release of IL-33, alum induced Th2 immunity via IL-5 and IL-13 production in group 2 innate lymphoid cells (ILC2s) and increased MHC class II expression in antigen-presenting cells (APCs) in the lung. Our results suggest that IL-33 secretion by epithelial cell necroptosis initiates APC- and ILC2-mediated T cell activation, which is important for the enhancement of Ag-specific IgA Ab production by alum.