IL-36 and IL-1/IL-17 Drive Immunity to Oral Candidiasis via Parallel Mechanisms

Abstract

Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. is a frequent human fungal pathogen causing mucosal infections. Although the initiators and effectors important in protective host responses to 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 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. In this study, we identify IL-36 cytokines as a new player in these responses. We show that infection of the oral mucosa induces the production of IL-36. As 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 infection.

IL-23 supports host defense against systemic Candida albicans infection by ensuring myeloid cell survival

“…Our results fit in a growing list of examples of additional roles for IL-23. A recent report suggested an IL-17-independent IL-23-dependent protective pathway in the context of experimental oropharyngeal candidiasis, which was linked to IL-36 [52]. Two other pivotal studies showed that IL-23 instructs IL-22 production, which in turn promotes dermal inflammation and acanthosis [19] and that IL-23 can drive GM-CSF production, which is essential for the induction of EAE [16,17].…”

A loss-of-function mutation in IL-17F enhances susceptibility of mice to oropharyngeal candidiasis

“…Even so, OPC susceptibility in mice does not perfectly phenocopy the human condition. Unlike nearly all humans (5, 86), laboratory mice do not harbor C. albicans as a commensal organism, and hence the acute OPC model system mainly reflects events in the innate response (59, 76, 78, 87). Mice lacking STAT3 in T cells are not susceptible to OPC (76).…”

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…The impact of these mechanisms in the epithelial immune responses to C. albicans is yet to be elucidated. et al, 2018), there is evidence available to suggest that IL-23 has IL-17-independent effects (Lee et al, 2015;Maxwell et al, 2015;Verma et al, 2018). These observations highlight the role of IL-36-mediated protection as an independent pathway contributing to immune mucosal protection to C. albicans infections .…”

“…While commensal yeasts or low hyphal burdens promote an activation of PI3K/Akt and NF-κB, with weaker, transient activation of p38, JNK, and ERK1/2 MAPK signaling pathways, detection of high levels of C. albicans hyphae results in the strong, sustained activation of all three MAPK pathways. This latter leads to activation of c-Fos within the AP-1 transcription factor and eventually, to the secretion of an array of antimicrobial peptides, alarmins, and pro-inflammatory cytokines (Moyes et al, 2010(Moyes et al, , 2014Verma et al, 2017bVerma et al, , 2018Nikou et al, 2019).…”