A stromal β-defensin, DEFB124, contributes to cutaneous host defense against Staphylococcus aureus.

Antimicrobial peptides (AMPs) are key components of barrier immunity and are traditionally attributed to epithelial cells and granulocytes. Here, we report human β-defensin 124 (DEFB124) as a previously uncharacterized AMP predominantly produced by dermal stromal cells. Transcriptomic analyses across independent therapeutic cohorts showed consistent induction of DEFB124 during the restoration of skin homeostasis in atopic dermatitis (AD). Spatial transcriptomics, qPCR, and protein analyses localized DEFB124 expression to dermal fibroblasts and adipocytes. The murine ortholog β-defensin 25 (Defb25) showed a similar stromal expression pattern, was induced following intradermal Staphylococcus aureus (S. aureus) challenge, and was suppressed by type 2 cytokines through IL-4 receptor signaling. Recombinant DEFB124 showed dose-dependent antimicrobial activity in vitro and reduced bacterial burden in vivo, whereas Defb25 mRNA knockdown impaired fibroblast antimicrobial capacity and exacerbated S. aureus infection. These findings expand the known repertoire of cutaneous β-defensins and reveal stromal cells as an important source of cutaneous antimicrobial defense.