Targeting keratinocyte DC-SIGN with heparin analogue octaparin restores barrier and immune homeostasis in atopic dermatitis.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dysregulated immune responses and impaired epidermal barrier function. A major therapeutic challenge is the identification of molecular targets capable of coordinately regulating both processes. Here, we identify dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) on keratinocytes as one such target. We demonstrate functional expression of DC-SIGN on keratinocytes and show that its engagement by a synthetic heparin analogue-exemplified by the oligosaccharide octaparin-produces profound therapeutic benefits. In a DNCB-induced murine model of AD, topical application of octaparin alleviated disease severity, suppressed both Th1- and Th2-type inflammatory responses, and restored expression of key epidermal barrier proteins such as filaggrin and loricrin. Metabolomic profiling further confirmed that octaparin treatment globally reversed disease-associated metabolic perturbations. Mechanistically, engagement of DC-SIGN on keratinocytes attenuated JAK-STAT signalling induced by key AD-associated cytokines, including IFN-γ and IL-4/IL-13. This attenuation led to reduced production of pro-inflammatory chemokines and cytokines, accompanied by increased expression of barrier-related genes. Critically, inhibition of DC-SIGN abolished the therapeutic effects of octaparin, establishing a causal requirement for this receptor. Our findings unveil a previously unrecognized role for keratinocyte DC-SIGN in coordinating immune and barrier responses and highlight it as a druggable target for novel therapeutic strategies in AD.