Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy.
Department of Scienza e Tecnologia del Farmaco, University of Turin, 10124 Turin, Italy.
Int J Mol Sci. 2024 Nov 19;25(22):12390. doi: 10.3390/ijms252212390.
Inducible T-cell costimulator (ICOS, CD278) is a costimulatory receptor primarily expressed by activated T cells. It binds to ICOS ligand (ICOSL, CD275), which is expressed by various immune and non-immune cell types, particularly in inflamed tissues. ICOSL can also bind to osteopontin (OPN), a protein that functions both as a component of the extracellular matrix and as a soluble pro-inflammatory cytokine. Previous studies, including ours, have shown that ICOS and ICOSL play a role in skin wound healing, as mice deficient in either ICOS or ICOSL exhibit delayed healing. The aim of this study was to investigate the involvement of the ICOS/ICOSL/OPN network in skin wound healing by analyzing mice that are single knockouts for ICOS, ICOSL, or OPN, or double knockouts for ICOS/OPN or ICOSL/OPN. Our results showed that wound healing is impaired in all single knockout strains, but not in the two double knockout strains. Cellular and molecular analyses of the wound healing sites revealed that the healing defect in the single knockout strains is associated with reduced neutrophil infiltration and decreased expression of α-SMA (a marker of myofibroblasts), IL-6, TNFα, and VEGF. In contrast, the normalization of wound closure observed in the double knockout strains was primarily linked to increased vessel formation. A local treatment with recombinant ICOS-Fc improved healing in all mouse strains expressing ICOSL, but not in those lacking ICOSL, and led to a local increase in vessel formation and macrophage recruitment, predominantly of the M2 type.
诱导型 T 细胞共刺激分子（ICOS，CD278）是一种共刺激受体，主要表达于活化的 T 细胞。它与 ICOS 配体（ICOSL，CD275）结合，ICOSL 表达于各种免疫细胞和非免疫细胞类型，特别是在炎症组织中。ICOSL 还可以与骨桥蛋白（OPN）结合，OPN 既是细胞外基质的组成部分，又是一种可溶性促炎细胞因子。以前的研究，包括我们的研究，表明 ICOS 和 ICOSL 在皮肤伤口愈合中发挥作用，因为缺乏 ICOS 或 ICOSL 的小鼠表现出愈合延迟。本研究旨在通过分析 ICOS、ICOSL 或 OPN 单一敲除小鼠、ICOS/OPN 或 ICOSL/OPN 双重敲除小鼠，研究 ICOS/ICOSL/OPN 网络在皮肤伤口愈合中的作用。我们的结果表明，所有单一敲除株的伤口愈合均受损，但在两种双重敲除株中则没有。对伤口愈合部位的细胞和分子分析表明，单一敲除株的愈合缺陷与中性粒细胞浸润减少和 α-SMA（肌成纤维细胞标志物）、IL-6、TNFα 和 VEGF 表达降低有关。相比之下，在双重敲除株中观察到的伤口闭合正常化主要与血管形成增加有关。在表达 ICOSL 的所有小鼠株中，局部给予重组 ICOS-Fc 可改善愈合，但在缺乏 ICOSL 的小鼠株中则没有，并且导致局部血管形成和巨噬细胞募集增加，主要是 M2 型。
