Botulinum toxin A prevents hypertrophic scarring by suppressing PARP14/SOCS2-mediated M2 polarization of macrophages.

Botulinum toxin A (BTXA) is a safe and widely used neurotoxic protein in cosmetic procedures and medical applications. This investigation focuses on the function of BTXA on macrophage phenotype during hypertrophic scar (HS) formation and the underlying functional mechanism. A mouse model of HS was generated, where BTXA treatment reduced dermal thickness, epidermal hyperplasia, and collagen deposition in a dose-dependent manner. Moreover, BTXA reduced fibrosis, proliferation, angiogenesis, and M2 macrophage markers within the scar tissues, with parallel findings obtained in the in vitro co-culture system of induced M2 macrophages (derived from THP-1 monocytes) and human dermal fibroblasts (HDFs). Following bioinformatics and RNA sequencing insights, we identified increased expression of poly (ADP-ribose) polymerase family member 14 (PARP14) and suppressor of cytokine signaling 2 (SOCS2) in wound skin of mice, which were suppressed by BTXA treatment. PARP14 enhanced SOCS2 mRNA stability. Overexpression of PARP14 restored the M2 polarization of macrophages and negated the HS-ameliorating effects of BTXA. However, these effects were counteracted by the additional silencing of SOCS2 in mice or THP-1 cells. In conclusion, this investigation suggests that BTXA inhibits PARP14-mediated SOCS2 RNA stabilization to reduce M2 polarization of macrophages and alleviate hypertrophic scarring.