Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Department of Medicine (Dermatology), Faculty of Medicine, Vajira Hospital, Navamindradhiraj University, Bangkok 10300, Thailand.
Int J Mol Sci. 2023 Jan 10;24(2):1376. doi: 10.3390/ijms24021376.
Prolonged inflammation and impaired re-epithelization are major contributing factors to chronic non-healing diabetic wounds; diabetes is also characterized by xerosis. Advanced glycation end products (AGEs), and the activation of toll-like receptors (TLRs), can trigger inflammatory responses. Aquaporin-3 (AQP3) plays essential roles in keratinocyte function and skin wound re-epithelialization/re-generation and hydration. Suberanilohydroxamic acid (SAHA), a histone deacetylase inhibitor, mimics the increased acetylation observed in diabetes. We investigated the effects of TLR2/TLR4 activators and AGEs on keratinocyte AQP3 expression in the presence and absence of SAHA. Primary mouse keratinocytes were treated with or without TLR2 agonist PamCys-Ser-(Lys) (PAM), TLR4 agonist lipopolysaccharide (LPS), or AGEs, with or without SAHA. We found that (1) PAM and LPS significantly upregulated AQP3 protein basally (without SAHA) and PAM downregulated AQP3 protein with SAHA; and (2) AGEs (100 µg/mL) increased AQP3 protein expression basally and decreased AQP3 levels with SAHA. PAM and AGEs produced similar changes in AQP3 expression, suggesting a common pathway or potential crosstalk between TLR2 and AGEs signaling. Our findings suggest that TLR2 activation and AGEs may be beneficial for wound healing and skin hydration under normal conditions via AQP3 upregulation, but that these pathways are likely deleterious in diabetes chronically through decreased AQP3 expression.
慢性非愈合性糖尿病创面的主要致病因素是炎症持续和再上皮化受损；糖尿病还伴有干燥症。晚期糖基化终产物（AGEs）和 Toll 样受体（TLRs）的激活可引发炎症反应。水通道蛋白 3（AQP3）在角质形成细胞功能和皮肤创面再上皮化/再生及水合作用中发挥重要作用。酰基辅酶 A 水解酶抑制剂（suberanilohydroxamic acid，SAHA）可模拟糖尿病中观察到的乙酰化增加。我们研究了 TLR2/TLR4 激活剂和 AGEs 在存在和不存在 SAHA 的情况下对角质形成细胞 AQP3 表达的影响。用或不用 TLR2 激动剂 PamCys-Ser-(Lys)（PAM）、TLR4 激动剂脂多糖（LPS）或 AGEs 处理原代小鼠角质形成细胞，有或没有 SAHA。我们发现：（1）PAM 和 LPS 显著地在基础水平上上调 AQP3 蛋白（无 SAHA），而 PAM 下调了 SAHA 存在时的 AQP3 蛋白；（2）AGEs（100μg/ml）在基础水平上增加了 AQP3 蛋白的表达，同时降低了 SAHA 存在时的 AQP3 水平。PAM 和 AGEs 对 AQP3 表达产生了相似的变化，这表明 TLR2 和 AGEs 信号之间存在共同的通路或潜在的串扰。我们的研究结果表明，TLR2 激活和 AGEs 可能通过上调 AQP3 而有益于正常情况下的创面愈合和皮肤水合，但这些通路在糖尿病慢性期通过下调 AQP3 表达可能是有害的。
