Betacellulin, a member of the EGF family, ameliorates atopic dermatitis-like symptoms via EGFR-JNK/ERK-mediated activation of autophagy

抄録

Background: The expression of betacellulin (BTC), which functions as a ligand for the EGF receptor (EGFR), is markedly reduced in the lesional skin of individuals with atopic dermatitis (AD), and it can improve Th2-type cytokine-mediated impairment of skin barrier function. However, the therapeutic potential of BTC in AD is poorly understood. Therefore, we sought to explore the therapeutic role and mechanisms of BTC in AD.

Methods: An MC903-induced AD mouse model was established to evaluate the therapeutic effects of BTC. Staphylococcus aureus internalization in human primary keratinocytes was assessed using fluorescein isothiocyanate labeling and immunofluorescence. In vivo S. aureus invasion was evaluated using a bacterial loading assay. An erlotinib-treated AD mouse model was used to investigate the involvement of EGFR signaling in the BTC-mediated alleviation of AD-like symptoms. Western blotting, immunofluorescence, and electron microscopy were used to assess BTC-induced autophagy. Conditional autophagy knockout mice were used to investigate the role of active autophagy in the therapeutic effects of BTC.

Results: BTC significantly ameliorated MC903-induced AD-like skin inflammation in a murine model, as evidenced by improvements in skin barrier function, reductions in inflammatory cytokine levels, and the suppression of S. aureus invasion. Mechanistically, BTC activates autophagy in keratinocytes through the EGFR-JNK/ERK signaling pathway. Importantly, the therapeutic effects of BTC were abolished in mice pretreated with an EGFR inhibitor and in mice with keratinocyte-specific autophagy deficiency.

Conclusions: BTC is a promising therapeutic candidate for AD through the activation of EGFR-JNK/ERK-dependent autophagy, highlighting the potential of BTC for clinical translation in AD management.