DNAJB2 Attenuates Rosacea Skin Inflammation and Angiogenesis by Inhibiting the Endoplasmic Reticulum Stress-mediated TLR2/Myd88/NF-κB pathway.

Abstract

Endoplasmic reticulum stress (ERS) has recently been proposed as a core factor in the pathogenesis and aggravation of rosacea. The roles of ERS-related genes in rosacea are largely unknown and were investigated in this study. Rosacea microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed ERS-related genes in rosacea patients vs. controls were screened using the Limma package, and LASSO regression was used to screen for characteristic genes. The infiltrating fraction was evaluated using ssGSEA. Clinical rosacea samples, age-matched healthy volunteers, and LL37-induced mice models were used to investigate the expression of DNAJB2 and its function. In the GSE65914 dataset, 17 differentially expressed ERS-related genes were screened. Of these, 13 were identified as characteristic genes predicting rosacea risk. The adaptive immune response, TLR signaling pathway, and chemokine signaling pathway were activated with a high risk of rosacea. After expression validation using the GSE155141 dataset, DNAJB2 was identified as a key gene. DNAJB2 expression was significantly decreased in both datasets, clinical samples, and the LL37-induced mice model. DNAJB2 overexpression could alleviate rosacea skin injury and inhibit expression of inflammatory cytokines and chemokines as well as angiogenesis. The infiltration levels of the majority of immune cell types were elevated in rosacea samples, and DNAJB2 overexpression inhibited CD4 + T cell infiltration, as well as Th1 and Th17 polarizing genes. Moreover, DNAJB2 could inhibit ERS marker proteins and the activated TLR2/Myd88/NF-κB pathway. DNAJB2 may be a novel target for rosacea treatment.