Bui Kacey Guenther, Chang Ya-Chu, Chiraphapphaiboon Wannasiri, Wang Jianfeng, Ebens Christen L, Bielinsky Anja-Katrin, Tolar Jakub, Nguyen Hai Dang
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
bioRxiv. 2025 Aug 11:2025.08.11.668806. doi: 10.1101/2025.08.11.668806.
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder characterized by fragile skin, blistering, and chronic wounds. Keratinocytes, the primary cells in the epidermis, are directly affected by persistent injury in RDEB, contributing to chronic inflammation. High mobility group box 1 (HMGB1) is elevated in the serum of individuals with RDEB. However, its role in keratinocyte inflammation remains unclear. Here, we report an increase in expression in keratinocytes at chronic wound sites compared to matched non-wounded skin from an RDEB individual, suggesting a potential link to local inflammation. Pharmacological inhibition of HMGB1 using inflachromene reduced lipopolysaccharide (LPS)-induced inflammatory responses in a keratinocyte cell line, supporting a role for keratinocyte-specific HMGB1 in inflammation. Surprisingly, deletion of alone or together with its paralogue did not suppress the inflammatory response to LPS. Furthermore, inflachromene still reduced inflammation in these knockout cells. This unexpected discrepancy between genetic deletion and pharmacologic inhibition points to a more complex role for HMGB1 or off-target effects of the compound. These findings suggest that HMGB1 may contribute to inflammation in keratinocytes, but its exact function needs further investigation.
隐性营养不良性大疱性表皮松解症（RDEB）是一种遗传性皮肤病，其特征为皮肤脆弱、水疱形成和慢性伤口。角质形成细胞是表皮中的主要细胞，在RDEB中会受到持续性损伤的直接影响，从而导致慢性炎症。高迁移率族蛋白B1（HMGB1）在RDEB患者的血清中水平升高。然而，其在角质形成细胞炎症中的作用仍不清楚。在此，我们报告，与来自一名RDEB个体的配对非伤口皮肤相比，慢性伤口部位角质形成细胞中的表达增加，这表明其与局部炎症存在潜在联系。使用炎色烯对HMGB1进行药理抑制可降低角质形成细胞系中脂多糖（LPS）诱导的炎症反应，这支持了角质形成细胞特异性HMGB1在炎症中的作用。令人惊讶的是，单独缺失 或与其旁系同源物 一起缺失并没有抑制对LPS的炎症反应。此外，炎色烯在这些基因敲除细胞中仍能减轻炎症。基因缺失与药理抑制之间的这种意外差异表明HMGB1具有更复杂的作用或该化合物存在脱靶效应。这些发现表明HMGB1可能对角质形成细胞中的炎症有贡献，但其确切功能需要进一步研究。
