Loss of GNB2L1 promotes expansion of CD74+ dendritic cells and contributes to development of diabetic foot ulcers.

Refractory diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation both locally and systemically. GNB2L1 has been reported to be associated with wound healing in diabetic rats, but the specific mechanism by which it acts has not been explored. scRNA-seq data from foot skin samples of three diabetic patients without DFU (non-DFU) and four diabetic patients with non-healing DFU (DFU) were downloaded from the GSE165816 dataset and analyzed. Twenty-five different cell clusters and fourteen cell types were identified, and the dendritic cell (DC) cluster was identified as a meaningful cell type. Skin wound tissues from 36 patients with DFU and 30 diabetic patients without DFU were collected. Based on gene signature analysis of the DC cluster, we identified a CD74+ DC subset with a high proportion in the DFU group in clinical samples. Moreover, enrichment analysis of differentially expressed genes in the DC cluster revealed that they were mainly related to infection, immune response, and ATP synthesis. GNB2L1 was identified as the most significantly down-regulated gene, and its expression level was negatively correlated with the wound healing time in DFU patients. A full-thickness dorsal wound model in db/db mice was established, and GNB2L1 upregulation promoted wound healing in db/db mice. CD74+ and CD74- DCs were isolated from blood samples of the above patients. CD74 upregulation promoted mitochondrial damage in DCs, which was reversed by GNB2L1 overexpression. In conclusion, GNB2L1 deficiency promotes CD74+ dendritic cell expansion and diabetic foot ulcer development.