IL-36 and IL-1/IL-17 drive immunity to oral candidiasis via parallel mechanisms

Akash H. Verma, Hanna Zafar, Nicole O. Ponde, Olivia W. Hepworth, Diksha Sihra, Felix E. Y. Aggor, Joseph S. Ainscough, Jemima Ho, Jonathan P. Richardson, Bianca M. Coleman, Bernhard Hube, Martin Stacey, Julian R. Naglik, Mandy J. McGeachy, Sarah L. Gaffen, Dave Moyes

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)


Protection against microbial infection by the induction of inflammation is a key function of the interleukin-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. Candida albicans is a frequent human fungal pathogen causing mucosal infections. Although the initiators and effectors important in protective host responses to C. albicans are well described, the key players in driving these responses remain poorly defined. Recent work has identified a central role played by IL-1 in inducing innate type 17 immune responses to clear C. albicans infections. Despite this, lack of IL-1 signaling does not result in complete loss of immunity, indicating that there are other factors involved in mediating protection to this fungus. Here, we identify IL-36 cytokines as a new player in these responses. We show that C. albicans infection of the oral mucosa induces the production of IL-36. In common with IL-1α/β, induction of epithelial IL-36 depends on the hypha-associated peptide toxin, Candidalysin. Epithelial IL-36 gene expression requires p38-MAPK/c-Fos, NF-κB and PI3K signaling, and is regulated by the MAPK phosphatase MKP1. Oral candidiasis in IL-36R-/- mice shows increased fungal burdens and reduced IL-23 gene expression, indicating a key role played by IL-36 and IL-23 in innate protective responses to this fungus. Strikingly, we observed no impact on gene expression of IL-17 or IL-17-dependent genes, indicating that this protection occurs via an alternative pathway to IL-1-driven immunity. Thus, IL-1 and IL-36 represent parallel epithelial cell-driven protective pathways in immunity to oral C. albicans infection.
Original languageEnglish
Pages (from-to)627-634
Number of pages8
JournalJournal of Immunology
Issue number2
Early online date9 Jul 2018
Publication statusPublished - 15 Jul 2018


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