Department of Dermatology, Venereology and Allergology, Max Bürger Research Centre, Medical Faculty, University Leipzig, Johannisallee 30, 04103 Leipzig, Germany.
Int J Mol Sci. 2024 Sep 16;25(18):9980. doi: 10.3390/ijms25189980.
Chronic non-healing wounds are characterized by persistent inflammation, excessive matrix-degrading proteolytic activity and compromised extracellular matrix (ECM) synthesis. Previous studies showed that S100A8/A9 are strongly dysregulated in delayed wound healing and impair the proper function of immune cells. Here, we demonstrate an unrecognized pathological function of overexpression in wounds with impaired healing that directly affects ECM functions in fibroblasts. S100A9 was analyzed in two different mouse models mimicking the features of the two most prominent types of non-healing wounds in humans. Db/db mice were used as a model for diabetes-associated impaired wound healing. Iron-overloaded mice were used to mimic the conditions of impaired wound healing in chronic venous leg ulcers. The skin wounds of both mouse models are characterized by delayed wound closure, high and sustained expression of pro-inflammatory mediators and a substantially decreased ECM deposition, all together the hallmarks of non-healing wounds in humans. The wounds of both mouse models also present a solid and prolonged expression of and that coincides with a compromised ECM deposition and that was confirmed in chronic wounds in humans. Mechanistically, we reveal that S100A9 directly affects ECM deposition by shifting the balance of expression of ECM proteins and ECM degrading enzymes in fibroblasts via toll-like-receptor 4-dependent signaling. Consequently, blocking S100A9 during delayed wound healing in db/db mice restores fibroblast ECM functions eliciting increased matrix deposition. Our data indicate that the dysregulation of S100A9 directly contributes to a compromised ECM deposition in chronic wounds and further suggests S100A9 as a promising therapeutic target to improve tissue repair in chronic wounds.
慢性非愈合性伤口的特征是持续的炎症、基质降解蛋白酶活性过度和细胞外基质（ECM）合成受损。先前的研究表明，S100A8/A9 在延迟性伤口愈合中强烈失调，并损害免疫细胞的正常功能。在这里，我们证明了 S100A9 过表达在愈合受损的伤口中的一种未被认识的病理功能，它直接影响成纤维细胞中 ECM 的功能。在两种模拟人类两种最主要的非愈合性伤口特征的不同小鼠模型中分析了 S100A9。Db/db 小鼠被用作糖尿病相关伤口愈合受损的模型。铁超负荷小鼠被用于模拟慢性静脉性腿部溃疡中伤口愈合受损的情况。这两种小鼠模型的皮肤伤口都表现为伤口闭合延迟、促炎介质持续高表达和 ECM 沉积显著减少，这些都是人类非愈合性伤口的特征。这两种小鼠模型的伤口也表现出 S100A9 的稳定和持续表达，这与 ECM 沉积受损一致，并且在人类慢性伤口中得到了证实。从机制上讲，我们揭示了 S100A9 通过 Toll 样受体 4 依赖性信号转导直接影响成纤维细胞中 ECM 蛋白和 ECM 降解酶的表达平衡，从而直接影响 ECM 沉积。因此，在 db/db 小鼠的延迟性伤口愈合过程中阻断 S100A9 可恢复成纤维细胞的 ECM 功能，引起基质沉积增加。我们的数据表明，S100A9 的失调直接导致慢性伤口中 ECM 沉积受损，并进一步表明 S100A9 是改善慢性伤口组织修复的一个有前途的治疗靶点。
