Cervantes Recalde Maria Fernanda, Bogensperger Elena Zoe, Hans Joachim, Stuhlmann Dominik, Somoza Veronika, Lieder Barbara
Institue of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna, Austria.
Front Pharmacol. 2025 Jul 21;16:1629941. doi: 10.3389/fphar.2025.1629941. eCollection 2025.
In the context of epidermal inflammation, the inflammatory response not only involves the release of inflammatory cytokines like interleukin 8 (IL-8), but also modulation of tight junction protein expression levels. Previous studies showed that the tight junction protein claudin 1 (CLDN1) is upregulated during tumor necrosis factor α (TNFα)-induced inflammation by capsaicin in keratinocytes in a transient receptor potential channel vanilloid 1 (TRPV1)-dependent manner. However, the caveat with TRPV1 ligands is the undesired pain response elicited by the activation of neuronal TRPV1 channels. In this study, we hypothesized that also less or non-pungent homovanillic acid esters as structural analogs of capsaicin target CLDN1 upregulation during inflammation.
We aimed to identify beneficial structural characteristics by selecting homovanillic acid esters with different aliphatic tail structures and screening them for CLDN1 upregulation at early stages of TNFα-induced inflammation in basal keratinocytes.
CLDN1 expression was upregulated independently of TRPV1 by compounds with a tail of 5 or 6 C-atoms, regardless of the presence of ramifications and double bonds with a maximum fold change of 2.05 ± 0.22 against control. The induction of CLDN1 expression was accompanied by increased expression of the differentiation marker involucrin (IVL).
The results suggest that the homovanillic ester-induced CLDN1 upregulation is a result of increased differentiation of the basal keratinocytes towards the keratinocyte morphology present in the stratum granulosum (SG), where tight junctions are formed. In conclusion, homovanillic acid esters with a 5 or 6 C-atom long aliphatic chain induced CLDN1 expression, thereby stimulating keratinocyte differentiation, independent from TRPV1 activation.
在表皮炎症的背景下，炎症反应不仅涉及白细胞介素8（IL-8）等炎性细胞因子的释放，还涉及紧密连接蛋白表达水平的调节。先前的研究表明，在肿瘤坏死因子α（TNFα）诱导的炎症过程中，辣椒素通过瞬时受体电位香草酸受体1（TRPV1）依赖性方式上调角质形成细胞中紧密连接蛋白claudin 1（CLDN1）的表达。然而，TRPV1配体的一个问题是激活神经元TRPV1通道会引发不必要的疼痛反应。在本研究中，我们假设作为辣椒素结构类似物的低刺激性或无刺激性的高香草酸酯在炎症过程中也靶向CLDN1上调。
我们旨在通过选择具有不同脂肪族尾部结构的高香草酸酯，并在基础角质形成细胞中TNFα诱导炎症的早期阶段筛选它们对CLDN1上调的作用，来确定有益的结构特征。
具有5或6个碳原子尾部的化合物可独立于TRPV1上调CLDN1的表达，无论是否存在分支和双键，与对照相比最大倍数变化为2.05±0.22。CLDN1表达的诱导伴随着分化标志物兜甲蛋白（IVL）表达的增加。
结果表明，高香草酸酯诱导的CLDN1上调是基础角质形成细胞向颗粒层（SG）中存在的角质形成细胞形态分化增加的结果，颗粒层中会形成紧密连接。总之，具有5或6个碳原子长脂肪链的高香草酸酯可诱导CLDN1表达，从而刺激角质形成细胞分化，独立于TRPV1激活。
