Is IL-17 signaling essential for mucosal defense against Candida?

IL-17 signaling is a crucial component of the body's mucosal immune system, serving as a non-redundant primary defense mechanism against fungal pathogens, specifically Candida albicans. Reduced activity within this cytokine network directly compromises barrier immunity and leads to increased clinical susceptibility to localized fungal infections.

Clinical and effectiveness evidence

• Genetic Loss-of-Function: Autosomal-recessive deficiencies in IL17RA, IL17RC, and the critical downstream adapter protein ACT1, alongside autosomal-dominant mutations in IL17F, present clinically as chronic mucocutaneous candidiasis (CMC).
• The S65L Polymorphism: The IL17F rs763780 (S65L) missense variant behaves as a dominant-negative mutant. It significantly impairs IL-17F homodimer and IL-17A/F heterodimer signaling, which directly correlates with elevated oral fungal burdens and a higher incidence of mucosal infections in patients.
• Secondary Pathway Failures: Upstream genetic defects that disrupt Th17 cell differentiation or function—such as STAT3 loss-of-function (Job's syndrome), STAT1 gain-of-function, or CARD9 deficiency—cause severe, recurrent candidiasis primarily due to the secondary depletion of functional IL-17.
• Pharmacologic and Autoimmune Blockade: Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) develop neutralizing autoantibodies against IL-17A and IL-17F, causing profound susceptibility to candidiasis. Similarly, therapeutic monoclonal antibodies targeting the IL-17 pathway (e.g., secukinumab, ixekizumab) for autoimmune conditions carry a well-documented two- to threefold increased risk of mild-to-moderate mucocutaneous candidiasis.

Mechanistic explanations

• Epithelial Activation and AMP Expression: IL-17A and IL-17F bind to the IL-17RA/IL-17RC receptor complex on barrier epithelial cells. This triggers downstream signaling cascades that upregulate antimicrobial peptides (AMPs), including $\beta$-defensins (BD-2 and BD-3), S100 proteins (S100A7/8/9), and lipocalin-2, which directly inhibit Candida growth, colonization, and yeast-to-hyphae transition.
• Chemokine and Neutrophil Recruitment: IL-17 pathway activation stimulates epithelial and stromal cells to release potent neutrophil-attracting chemokines, such as CXCL1, CXCL2, CXCL5, and CXCL8 (IL-8), along with granulocyte colony-stimulating factor (G-CSF). Rapid and robust recruitment of neutrophils to the infection site is essential for engulfing and killing invading fungal hyphae.

Bottom line

IL-17 signaling is an indispensable immunological axis that protects mucosal surfaces by reinforcing epithelial barriers, inducing antimicrobial peptides, and recruiting neutrophils. Any genetic or pharmacological disruption to this pathway impairs these localized defense programs, significantly increasing susceptibility to mucosal and cutaneous Candida infections.