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Lookup NU author(s): Professor John Common
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2025 The Authors.Although NLRP3 has been extensively studied in myeloid cells, its existence and regulation in epithelial cells, including keratinocytes, are unclear. In fact, whether human keratinocytes express a functional NLRP3 inflammasome at all remains a matter of debate in the inflammasome field. In this study, we provide additional evidence that NLRP3 is repressed in human keratinocytes cultured under noninflammatory conditions but can be sharply induced by IFNγ—but not lipopolysaccharide. In this IFNγ-primed state, not all established NLRP3 activators are specific to NLRP3. We report that nigericin-driven keratinocyte pyroptosis occurs through both NLRP1 and NLRP3, whereas Staphylococcus aureus α-hemolysin exclusively and nonredundantly activates NLRP3, even though both require K+ efflux. Furthermore, in the presence of T cells, certain virulent S aureus strains can cause NLRP3-dependent pyroptotic death in keratinocytes in vitro through the cooperative actions of superantigens and α-hemolysin. In summary, our findings establish the strict inducibility and functional relevance of the NLRP3 inflammasome in nonmyeloid, epithelial cells in vitro. These results resolve conflicting reports and position keratinocytes as a context-specific, nonhematopoietic cellular model for studying NLRP3 activation in host–microbe interactions at barrier tissues.
Author(s): Rozario P, Lim YS, Ding SLS, Firdaus MJ, Wearne S, Wong BHS, Chua R, Robinson KS, Chu TSJ, Liu M, Cai SSC, Tan STE, Wee SK, Lamers MM, Verma NK, Xia Y, Yap EPH, Common JEA, Zhong F
Publication type: Article
Publication status: Published
Journal: Journal of Investigative Dermatology
Year: 2026
Pages: Epub ahead of print
Online publication date: 12/12/2025
Acceptance date: 05/11/2025
Date deposited: 12/01/2026
ISSN (print): 0022-202X
ISSN (electronic): 1523-1747
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.jid.2025.11.019
DOI: 10.1016/j.jid.2025.11.019
PubMed id: 41389956
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