1. Oral epithelial IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral mucosal candidiasis
- Author
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Daniel H. Kaplan, Partha S. Biswas, Felix E. Y. Aggor, Michail S. Lionakis, Natasha Whibley, Wei Shan, Jay K. Kolls, Vincent M. Bruno, Rachel D. Bailey, Bianca M. Coleman, Amol C. Shetty, Scott K. Durum, Carrie McCracken, Sarah L. Gaffen, Julian R. Naglik, Giraldina Trevejo-Nunez, and Timothy J. Break
- Subjects
0301 basic medicine ,Male ,STAT3 Transcription Factor ,Immunology ,Biology ,Oropharyngeal Candidiasis ,Article ,Interleukin 22 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immunity ,Candidiasis, Oral ,Candida albicans ,medicine ,Animals ,Immunology and Allergy ,Oral mucosa ,STAT3 ,Mice, Knockout ,Interleukins ,Interleukin-17 ,Mouth Mucosa ,Epithelial Cells ,General Medicine ,biology.organism_classification ,Epithelium ,Mice, Inbred C57BL ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,STAT protein ,Cancer research ,biology.protein ,Female ,030215 immunology ,Signal Transduction - Abstract
Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans. IL-17 and IL-22 both mediate antifungal immunity yet activate distinct downstream signaling pathways. While much is known about IL-17-dependent immunity in OPC, the activities of IL-22 are less well delineated. We show that induction of Il22 is independent of Dectin-1, CARD9 and aryl hydrocarbon receptor (AhR) and is driven by IL-23 and the C. albicans pore forming peptide candidalysin. Despite similar induction requirements and cellular sources, IL-22 and IL-17 function non-redundantly during OPC and exert opposing roles in neutrophil recruitment. The IL-22 and IL-17 receptors are required in anatomically distinct locations; loss of IL-22RA1 in the oral basal epithelial layer (BEL) but not the suprabasal epithelial layer (SEL) causes susceptibility to OPC, whereas IL-17RA is needed in the SEL. Our data reveal that IL-22 is a major activator of STAT3 in the BEL during OPC. Moreover, loss of STAT3 in the BEL but not the SEL renders mice susceptible to OPC. Transcriptional profiling of RNASeq data linked IL-22/STAT3 to oral epithelial cell proliferation and survival, but also, unexpectedly, to driving an IL-17 gene signature. We show that IL-22 acts on the BEL to replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to respond to IL-17. Consequently, IL-22 signaling in BEL ‘licenses’ IL-17R signaling in the oral epithelium, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis. This work also suggests that oral thrush in Jobs’ syndrome patients may be caused by STAT3 impairments in the oral epithelium, not just Th17 cells.
- Published
- 2020