Dysregulated NAMPT signaling underlines the immune-suppressive microenvironment in venous leg ulcers
Abstract
Venous leg ulcers (VLUs) are the most common form of lower extremity ulceration, with a rising prevalence among the elderly. Despite their clinical significance, the molecular mechanisms underlying VLU remain poorly defined. In this study, we constructed a comprehensive single-cell transcriptional atlas of VLUs, unveiling a widespread immunosuppressive microenvironment within the lesions. Specifically, stromal cells exhibited attenuated inflammatory responses coupled with enhanced fibrotic activity. Keratinocytes and endothelial cells demonstrated increased proliferative and angiogenic activity, respectively, yet both cell types showed markedly reduced antigen-presenting capacity. Immune cell compartments displayed profound dysfunction characterized by marked reductions and impaired functionality of dendritic cells, polarization of macrophages toward an anti-inflammatory M2 phenotype, and enrichment of T cell exhaustion signatures. Notably, cell–cell communication analysis revealed diminished crosstalk between immune and structural cell populations. Mechanistically, we identified NAMPT-mediated signaling as a critical regulator of myeloid-stromal crosstalk. Targeted depletion of NAMPT in macrophages disrupted fibroblast-mediated inflammatory responses and impaired wound healing, whereas exogenous NAMPT administration reactivated immune responses and promoted tissue repair in chronic wounds. Collectively, these findings provide a comprehensive molecular framework for understanding immune–stromal dysfunction in VLUs and position NAMPT as a central immune regulator and promising therapeutic target for chronic wound treatment.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Jiating Wang
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Lei Guo
Quantitative Biomedical Research Center, Department of Health Science & Biostatistics, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Yunxi Tao
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Yunting Xiao
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Yejing Huang
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Ling Pan
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Chen Lyu
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Liping Zhu
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Xiya Zhang
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Juan Gao
Institute of Soil Science, Chinese Academy of Sciences , ,
Chunyan Cao
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Zhuang Liu
Macao Institute of Materials Science and Engineering
Ning Xu Landén
Dermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet
Jing Wang
Hunan Cancer Hospital Changsha China
Tongbin Chu
Department of Wound Regeneration, The Second Hospital of Dalian Medical University
Xinfeng Wu
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Hongsheng Wang
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College
Dongqing Li
Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College