AUTHOR=Kurosaka Shiho , Tanno Hiromasa , Hirose Minako , Kamada Wakana , Takayashiki Rena , Sone Ikue , Sato Yuki , Watanabe Takumi , Ishi Shinyo , Shoji Miki , Imai Yoshimichi , Sato Ko , Ishii Keiko , Hara Hiromitsu , Yamasaki Sho , Saijo Shinobu , Iwakura Yoichiro , Kawakami Kazuyoshi , Kanno Emi 

TITLE=Contribution of CARD9 signaling to wound healing in skin promoted by topical administration of heat-killed Enterococcus faecalis strain KH2 and the involvement of Dectin-2

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1550934

DOI=10.3389/fimmu.2025.1550934

ISSN=1664-3224

ABSTRACT=IntroductionLactic acid bacteria (LAB) are well known for their beneficial effects on the regulation of immune responses and host protection against microbial infections. We previously reported that heat-killed Enterococcus faecalis strain KH2 (heat-killed KH2), a species of LAB, enhances inflammatory responses at wound sites and accelerates the skin wound healing process. In this study, we aimed to clarify the pathway underlying the wound-healing effects of heat-killed KH2. We focused on CARD9, a common adaptor molecule for C-type lectin receptors and Dectin-2, the upstream receptor for this adaptor molecule.MethodsFour full-thickness dermal wounds were created on the backs of wild-type (WT) mice, CARD9 KO mice, and Dectin-2 KO mice, and the effects of heat-killed KH2 administration were examined. We analyzed the percent wound closure, re-epithelialization, granulation tissue formation, and the production of inflammatory cytokines and chemokines.ResultsHeat-killed KH2 administration enhanced wound closure, granulation tissue formation, and re-epithelialization in WT mice. However, these effects were absent in heat-killed KH2-treated CARD9 KO mice. Similar results were observed in the migration of neutrophils and the production of TNF-α, IL-6, KC, and MIP-2 in heat-killed KH2-treated CARD9 KO mice. Furthermore, heat-killed KH-2 induced activation of reporter cells expressing Dectin-2. Finally, heat-killed KH-2 treatment in Dectin-2 KO mice did not promote skin wound healing.ConclusionThese results suggest that recognition of heat-killed KH2 by Dectin-2 may activate CARD9-mediated signaling, which may contribute to the promotion of skin wound healing through KH2 treatment.