Staphylococcus epidermidis prevents UV-induced skin aging by suppressing TLR3-mediated senescence

Ultraviolet (UV) radiation is a major environmental driver of skin photoaging and induces keratinocyte senescence accompanied by the release of senescence-associated secretory phenotype (SASP) factors that promote dermal degeneration. However, whether and how skin commensal bacteria modulate UV-induced senescence remains incompletely understood. Here, we investigated the potential role of Staphylococcus epidermidis, a dominant epidermal commensal, in regulating UV-induced skin photoaging. In a murine photoaging model, intradermal or topical administration of a ≤10 kDa fraction derived from S. epidermidis culture supernatant attenuated epidermal hyperplasia, collagen degradation, and the expression of senescence-associated markers following long-term UV exposure. In keratinocytes, UVB irradiation induced reactive oxygen species accumulation, DNA damage, and robust production of SASP factors that promoted paracrine senescence in dermal fibroblasts. Treatment with S. epidermidis or its candidate bioactive lipopeptide component LP78 markedly reduced these responses. Genetic deletion or silencing of Toll-like receptor 3 (Tlr3) diminished UV-induced SASP factor production and fibroblast senescence, supporting a role of TLR3 in photoaging-associated inflammatory signaling. Mechanistically, S. epidermidis and LP78 activated TLR2 signaling to induce TNF receptor-associated factor 1 (TRAF1), a negative regulator of TLR3, thereby suppressing TLR3-mediated SASP production. Collectively, these findings identify a potential microbiota-innate immune regulatory axis in which S. epidermidis-derived factors restrain keratinocyte inflammatory senescence and attenuate UV-induced skin damage. This work highlights a potential role of commensal bacteria in limiting photoaging-associated inflammation.