Hyperglycemia promotes maladaptive Dectin-1 signaling and impairs skin antifungal host defense.

Abstract

People with chronic hyperglycemia are more susceptible to fungal skin infections, yet the mechanisms behind worse clinical outcomes remain unclear. Using both in vivo and in vitro models, we explored how hyperglycemia affects skin antifungal defenses. Hyperglycemic mice showed increased susceptibility to Candida albicans skin infections, with larger lesions and higher fungal loads at all time points tested. Histology revealed larger abscesses, more extensive myeloid cell infiltration, and poorer control of fungal invasion, all associated with increased chemoattractant production on day 1 post-infection. Glucose reduction with the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide reduced lesion size and fungal burden in infected diabetic mice, linking metabolic control to the restoration of innate immune function. Phagocytes and keratinocytes exposed to high glucose exhibited inhibited fungal ingestion. RNA-seq analysis of C. albicans -infected dermal macrophages cultured under high-glucose conditions showed enrichment of genes related to the C-type lectin receptor pathway, including Clec7a (Dectin-1), and also revealed inhibition of downstream signaling pathways required for effective phagocytosis. Pharmacologic blockade or genetic deletion of Dectin-1 restored fungal uptake under high-glucose conditions and improved host defense in vivo . Dectin-1 signaling in hyperglycemia increased prostaglandin E2 (PGE2) production along with increased abundance of microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of PGE2 synthesis rescued deficient phagocytic function. These findings identify maladaptive innate immune sensing as a key mechanism underlying susceptibility to fungal infection in diabetes and reveal how metabolic stress converts antifungal recognition pathways into drivers of inflammatory dysfunction.

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