Contribution of HMGB1 to Keratinocyte inflammation in Recessive Dystrophic Epidermolysis Bullosa

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 HMGB1 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 HMGB1 alone or together with its paralogue HMGB2 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.