Defensins–thioredoxin crosstalk in innate immunity: A redox switch linking barrier defense, inflammation, and disease

Defensins are cysteine-rich innate immune effector peptides that support antimicrobial defense, immune regulation, and mucosal homeostasis. Because these activities occur within redox-sensitive environments, a functional relationship may exist between defensin biology and the thioredoxin (Trx)/thioredoxin-interacting protein (TXNIP) axis. The strongest direct evidence is Trx1-mediated reduction of human β-defensin 1 (hBD1), which enhances its antimicrobial activity. Accordingly, this review examines the redox-sensitive interfaces linking defensin-associated responses with the Trx1/TXNIP axis. Redox-sensitive interfaces examined in detail include TLR/NF-κB signaling pathways, dendritic cell maturation, nutrient-sensitive antimicrobial secretion, and IL-22/STAT3-dependent Paneth-cell responses. These relationships are subtype-, isoform-, species-, and model-specific, with varying degrees of direct and indirect support. These interactions may be particularly relevant in diseases involving epithelial stress, microbial imbalances, and dysregulated innate immune activation. A deeper understanding of these interfaces may provide insight into redox-based mechanisms controlling innate immunity and translational applications in inflammatory diseases.