Dysregulation of DPP4-CXCL12 Balance by TGF-β1/SMAD Pathway Promotes CXCR4+ Inflammatory Cell Infiltration in Keloid Scars

ZongAn Chen,1,* Zhen Gao,1,* LingLing Xia,1 XiaoQing Wang,2,* LiMing Lu,3,* XiaoLi Wu1,* 1Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Orthopedics, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 3Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: XiaoLi WuDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of ChinaTel +86-2163089567Email wuxiaoli528@126.comPurpose: Recent studies have confirmed the important role of chronic inflammation in keloid; however, mechanism of chronic inflammation in keloid tissue remains largely unclear, especially the dynamic of infiltrated inflammatory cells.Patients and Methods: Tissue and blood samples collected from keloid patients and healthy subjects were studied by immunohistochemistry and flow cytometry. Fibroblasts from keloid scars and normal skin were isolated by enzymic digestion.Results: We found that CXCL12 expression was elevated which was correlated with decreased dipeptidyl peptidase-4 (DPP4) expression in keloid scars relative to mature scars. In vitro studies suggested that autocrine transforming growth factor β 1 (TGF-β 1) in keloid-derived fibroblasts negatively regulated DPP4 expression which inhibited the reduction of extracellular CXCL12 levels by DPP4. Furthermore, immunofluorescence showed that most fibroblasts in keloid scars were DPP4lowTGFβ 1high compared with DPP4highTGFβ 1low fibroblasts in normal skin tissue, which facilitated extracellular CXCL12 accumulation in fibroblasts in keloid scars. Furthermore, we found that most circulating leukocytes in peripheral blood and tissue-infiltrated inflammatory cells in keloid scars expressed the C-X-C motif chemokine receptor 4 (CXCR4) instead of CXCR7, indicating that the chemotaxis driven by CXCL12 is likely to be mediated mainly by CXCR4.Conclusion: Our study indicated that the TGF-β/DPP4/CXCL12 axis may contribute to chronic inflammation in keloid scars by recruiting inflammatory cells through the CXCR4 receptor.Keywords: keloid, chemokines, inflammation, DPP4, CXCL12, TGF-β