Localization-dependent effects of HSPA1A overexpression on skin inflammation and remodeling in a DNCB- induced mouse model of allergic dermatitis

Abstract Background Allergic dermatitis (AD) is a chronic relapsing inflammatory skin disorder, and current therapies remain symptomatic. Heat shock protein 70 (HSP70) exerts pro- or anti-inflammatory effects depending on its localization, yet its role in AD remains unclear. This study aimed to determine how overexpression of human HSPA1A with predominantly intracellular or extracellular accumulation affects skin inflammation and remodeling. Methods and Results Dermatitis was induced by topical 2,4-dinitrochlorobenzene (DNCB) in 81 male mice: wild-type C57BL/6J (WT) and transgenic (Tg(HSP70[in])) (intracellular) and (Tg(HSP70[out])) (extracellular) lines (n = 27 per genotype). Skin was collected on Days 0, 11, and 17 (n = 9 per genotype per time point) and examined by histochemical staining and immunofluorescence for HSP70, α-SMA, and COL1A1. On Day 11, epidermal thickness was lower in both transgenic lines than in WT mice; by Day 17, it was lowest in (Tg(HSP70[out])) mice. On Day 11, HSP70out mice showed the smallest increase in dermal cellularity and fewer α-SMA-positive microvessels than WT mice, and elastic fibers were partially preserved. In (Tg(HSP70[in])) mice, mast cell numbers rose sharply by Day 17, exceeding those in the other groups, and focal COL1A1 accumulation was most pronounced. Conclusions The effects of HSPA1A overexpression on DNCB-induced dermatitis depend on protein localization: extracellular accumulation was associated with faster resolution of inflammation and attenuated epidermal hyperplasia, whereas intracellular accumulation was associated with more persistent inflammatory changes. These findings identify extracellular HSP70 as a candidate modulator of skin repair in AD, although the underlying mechanisms require direct validation.