Single-cell analysis reveals melanocytes may promote inflammation in chronic wounds through cathepsin G

Abstract

During acute wound (AW) healing, a series of proper communications will occur between different epidermal cells at precise temporal stages to restore the integrity of the skin. However, it is still unclear what variation happened in epidermal cell interaction in the chronic wound environment. To provide new insights into chronic wound healing, we reconstructed the variations in the epidermal cell-cell communication network that occur in chronic wound healing via single-cell RNA-seq (scRNA-seq) data analysis. We found that the intricate cellular and molecular interactions increased in pressure ulcer (PU) compared to AW, especially the PARs signaling pathways were significantly upregulated. It shows that the PARs signaling pathways’ main source was melanocytes and the CTSG-F2RL1 ligand-receptor pairs were its main contributor. Cathepsin G (CatG or CTSG) is a serine protease mainly with trypsin- and chymotrypsin-like specificity. It is synthesized and secreted by some immune or non-immune cells. Whereas, it has not been reported that melanocytes can synthesize and secrete the CTSG. F2R Like Trypsin Receptor 1 (F2RL1) is a member of proteinase-activated receptors (PARs) that are irreversibly activated by proteolytic cleavage and its stimulation can promote inflammation and inflammatory cell infiltration. In this study, we found that melanocytes increased in pressure ulcers, melanocytes can synthesize and secrete the CTSG and may promote inflammation in chronic wounds through CTSG-F2RL1 pairs, which may be a novel potential target and a therapeutic strategy in the treatment of chronic wounds.

Decoding the Human Epidermal Complexity at Single-Cell Resolution

“…CTSG is a serine protease mainly expressed by melanocytes and involved in inflammation, while F2RL1 is widely expressed by fibroblasts and keratinocytes, where it plays an important role as a driver of inflammatory response. These data suggest that PARs might represent an important therapeutic target [54,78].…”

“…Understanding the complex human wound-healing mechanisms would greatly impact the success of diagnosis and therapy of both acute and chronic wounds. ScRNA-seq data generated from chronic wounds represent a powerful tool, offering new perspectives on the healing process [37,41,54].…”

“…Fibroblast-secreted WNT5A was identified as the ligand interacting with receptors FZD6 and FZD7 expressed by the basal layer's keratinocytes [49]. Yakupu et al took advantage of CellChat to provide new insights into PU cellular connections, using data from Li et al [41,54]. This analysis revealed that intercellular communication is enhanced in both number and strength, mostly between spinous keratinocytes and other clusters in PU, compared with AW samples.…”

“…The authors suggested that, in PU, spinous and mitotic cells mainly receive signals from melanocytes. In particular, the protease-activated receptor (PAR) signaling pathway mediated by the CTSG-F2RL1 ligand-receptor pair is one of the most activated in PU [54]. CTSG is a serine protease mainly expressed by melanocytes and involved in inflammation, while F2RL1 is widely expressed by fibroblasts and keratinocytes, where it plays an important role as a driver of inflammatory response.…”