Okuno Ryoko, Ito Yuko, Eid Nabil, Otsuki Yoshinori, Kondo Yoichi, Ueda Koichi
Deparment of Plastic and Reconstructive Surgery, Osaka Medical College, Osaka, Takatsuki, Japan.
Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Osaka, Takatsuki, Japan.
Histol Histopathol. 2018 Oct;33(10):1075-1087. doi: 10.14670/HH-18-005. Epub 2018 May 29.
Keloid is a fibro-proliferative skin disorder with tumor-like behavior and dependence on anaerobic glycolysis (the Warburg effect), but its exact pathogenesis is unknown. Although autophagy is widely accepted as a lysosomal pathway for cell survival and cellular homeostasis (specifically upon exposure to stressors such as hypoxia), very few studies have investigated the involvement of autophagy and related glycolytic effectors in keloidogenesis. Here the authors examined the expression and cellular localization of autophagy proteins (LC3, pan-cathepsin), glycolytic markers (LDH, MCT1, MCT4) and the transcription factor HIF isoforms in human keloid samples using immunohistochemical analysis and double-labeling immunofluorescence methods. Based on H&E staining and expression of CD31, keloids were compartmentalized into hypoxic central and normoxic marginal zones. Vimentin-expressing fibroblasts in the central zone exhibited greater autophagy than their marginal-zone counterparts, as evidenced by increased LC3 puncta formation and co-localization with lysosomal pan-cathepsin. LDH (a lactate stimulator), MCT4 (a lactate exporter) and HIF-1 α expression levels were also higher in central-zone fibroblasts. Conversely, HIF-2 α expression was upregulated in fibroblasts and endothelial cells of the peripheral zone, while MCT1 was expressed in both zones. Taken together, these observations suggest that upregulation of autophagy and glycolysis markers in keloid hypoxic-zone fibroblasts may indicate a prosurvival mechanism allowing the extrusion of lactate to marginal-zone fibroblasts via metabolic coupling. The authors believe this is the first report on differential expression of autophagic and glycolytic markers in keloid-zone fibroblasts. The study results indicate that autophagy inhibitors and MCT4 blockers may have therapeutic implications in keloid treatment.
瘢痕疙瘩是一种具有肿瘤样行为且依赖无氧糖酵解（瓦伯格效应）的纤维增生性皮肤病，但其确切发病机制尚不清楚。尽管自噬被广泛认为是细胞存活和细胞稳态的溶酶体途径（特别是在暴露于缺氧等应激源时），但很少有研究调查自噬和相关糖酵解效应器在瘢痕疙瘩形成中的作用。在这里，作者使用免疫组织化学分析和双标记免疫荧光方法，检测了人类瘢痕疙瘩样本中自噬蛋白（LC3、组织蛋白酶泛抗体）、糖酵解标志物（乳酸脱氢酶、单羧酸转运蛋白1、单羧酸转运蛋白4）和转录因子低氧诱导因子异构体的表达及细胞定位。基于苏木精-伊红染色和CD31的表达，瘢痕疙瘩被划分为缺氧的中央区和正常氧合的边缘区。中央区表达波形蛋白的成纤维细胞比边缘区的成纤维细胞表现出更强的自噬，LC3斑点形成增加以及与溶酶体组织蛋白酶泛抗体共定位证明了这一点。中央区成纤维细胞中乳酸脱氢酶（一种乳酸刺激物）、单羧酸转运蛋白4（一种乳酸转运体）和低氧诱导因子-1α的表达水平也更高。相反，低氧诱导因子-2α在周边区的成纤维细胞和内皮细胞中表达上调，而单羧酸转运蛋白1在两个区域均有表达。综上所述，这些观察结果表明，瘢痕疙瘩缺氧区成纤维细胞中自噬和糖酵解标志物的上调可能表明一种促存活机制，即通过代谢偶联将乳酸排至边缘区成纤维细胞。作者认为这是关于瘢痕疙瘩区成纤维细胞自噬和糖酵解标志物差异表达的首次报道。研究结果表明，自噬抑制剂和单羧酸转运蛋白4阻滞剂可能对瘢痕疙瘩治疗具有重要意义。
