Red Light Promotes Dermis-Epidermis Remodeling via TGFβ and AKT-Mediated Collagen Dynamics in Naturally Aging Mice

Noninvasive light therapy has been clinically demonstrated to replenish collagen and improve skin health. However, the underlying molecular mechanisms by which light therapy reverses collagen-related degenerative changes in the skin remain largely unclear. In this study, using a natural aging mouse model, red light, unlike other wavelengths, acutely increased dermal thickness and epidermal renewal, significantly improving the skin morphology of aging mice by enhancing collagen production in dermal fibroblasts and promoting collagen/integrin signaling-induced proliferation and differentiation of epidermal keratinocytes. Mechanistically, upregulation of endogenous TGFβ by red light in dermal fibroblasts promotes type I collagen mRNA and protein expression through activating SMAD2/3/4 translocation into the nucleus. Simultaneously, activated AKT by red light-induced cAMP inhibits type I collagen degradation via the downregulation of MMP expression in a NFR2/HO-1 dependent pathway. Then, the generated type I collagen in dermal fibroblasts induces the self-renewal ability (proliferation and differentiation) of epidermal keratinocytes through adhesion molecule integrin signaling. Importantly, red light-induced activation of AKT promotes fibroblast proliferation, thereby amplifying type I collagen production and subsequently facilitates collagen-mediated epidermal renewal. Thus, our work unveils the mechanisms of type I collagen-driven dermis-epidermis remodeling mediated by red light-activated endogenous TGFβ and AKT, suggesting a safe target for the prevention and treatment of skin degeneration.