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转化生长因子-β1/信号转导和转录激活因子通路导致的二肽基肽酶4-趋化因子配体12平衡失调促进瘢痕疙瘩中趋化因子受体4炎性细胞浸润

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

作者信息

Chen ZongAn, Gao Zhen, Xia LingLing, Wang XiaoQing, Lu LiMing, Wu XiaoLi

机构信息

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.

Department of Orthopedics, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.

出版信息

J Inflamm Res. 2021 Aug 26;14:4169-4180. doi: 10.2147/JIR.S326385. eCollection 2021.

DOI:10.2147/JIR.S326385
PMID:34483675
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8408422/
Abstract

PURPOSE

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 β1 (TGF-β1) 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 DPP4TGFβ1 compared with DPP4TGFβ1 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.

摘要

目的

近期研究已证实慢性炎症在瘢痕疙瘩中起重要作用；然而，瘢痕疙瘩组织中慢性炎症的机制仍不清楚，尤其是浸润性炎症细胞的动态变化。

患者和方法

通过免疫组织化学和流式细胞术对瘢痕疙瘩患者和健康受试者采集的组织和血液样本进行研究。通过酶消化法分离瘢痕疙瘩瘢痕和正常皮肤的成纤维细胞。

结果

我们发现，相对于成熟瘢痕，瘢痕疙瘩瘢痕中CXCL12表达升高，且与二肽基肽酶-4（DPP4）表达降低相关。体外研究表明，瘢痕疙瘩来源的成纤维细胞中自分泌转化生长因子β1（TGF-β1）负向调节DPP4表达，而DPP4表达受抑制会阻碍细胞外CXCL12水平的降低。此外，免疫荧光显示，与正常皮肤组织中DPP4+TGFβ1成纤维细胞相比，瘢痕疙瘩瘢痕中的大多数成纤维细胞为DPP4-TGFβ1，这促进了瘢痕疙瘩瘢痕中细胞外CXCL12在成纤维细胞中的积累。此外，我们发现外周血中大多数循环白细胞以及瘢痕疙瘩瘢痕中组织浸润性炎症细胞表达C-X-C基序趋化因子受体4（CXCR4）而非CXCR7，这表明由CXCL12驱动的趋化作用可能主要由CXCR4介导。

结论

我们的研究表明，TGF-β/DPP4/CXCL12轴可能通过CXCR4受体募集炎症细胞，从而导致瘢痕疙瘩瘢痕中的慢性炎症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4aea/8408422/7ebd7cce70b5/JIR-14-4169-g0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4aea/8408422/7ebd7cce70b5/JIR-14-4169-g0007.jpg

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