Lipoteichoic acid as a key wound healing mediator in Gram-positive bacteria

Lactobacillus species are probiotic Gram-positive bacteria known to exert regenerative effects on cutaneous wounds. However, the key components and underlying mechanisms responsible for these effects remain poorly defined. To identify the bioactive components responsible for wound healing, lipoteichoic acid (LTA), lipoprotein, and peptidoglycan were purified from Lactiplantibacillus plantarum and the purified molecules were administered intradermally in a murine excisional wound splinting model. Among them, only LTA significantly accelerated dermal wound healing. Histological analysis confirmed faster wound closure in LTA-treated mice compared to the control. The LTA/clodronate-liposome group exhibited attenuated wound area reduction compared to the LTA/vehicle-liposome-treated group, indicating the critical role of phagocytes including macrophages. LTA increased M2 macrophage markers such as arginase-1 and IL-10 in wound tissues. In vitro, LTA promoted the polarization of M0 and M1 macrophages toward the M2 phenotype (F4/80⁺CD11b⁺CD206⁺), while reducing M1-associated markers (CD86⁺CD206^-). The wound healing effects of LTA were substantially blocked by inhibitors for M2 macrophage polarization or arginase expression. To elucidate the role of Toll-like receptor 2 (TLR2) signaling in LTA-mediated wound healing, we employed TLR2-deficient mice. The wound healing effects of LTA were abolished in these mice, indicating that LTA-mediated wound healing is TLR2-dependent. Furthermore, LTAs from probiotics and other Gram-positive bacteria including Staphylococcus aureus also enhanced wound healing. Collectively, these findings suggest that LTAs accelerate wound healing by promoting M2 macrophage polarization through a TLR2-dependent pathway. This mechanism provides a potential therapeutic strategy for the treatments of skin injuries.