The molecular control of inflammation and epidermal thickening in skin lesions of patients with Atopic Dermatitis (AD) is not known. Sequestosome 1/p62 is a multifunctional adapter protein implicated in the control of key regulators of cellular homeostasis, such as pro-inflammatory and mTOR signaling.
The objective of this study was determine whether p62 plays a role in the cutaneous and systemic manifestations of an AD-like mouse model.
AD-like skin lesions were induced by deletion of JunB/AP-1 specifically in epidermal keratinocytes (JunB). The contribution of p62 to pathological changes was determined by inactivation of p62 in JunBp62 double knock-out (DKO) mice.
Expression of p62 was elevated in skin lesions of JunB mice, resembling upregulation of p62 in AD and psoriasis. When p62 was inactivated, JunB-associated defects in the differentiation of keratinocytes, epidermal thickening, skin infiltration by mast cells and neutrophils, and the development of macroscopic skin lesions were significantly reduced. p62 inactivation had little effect on circulating cytokines, but decreased serum IgE. Signaling through mTOR and NF-κB was increased in JunB but not in DKO skin, indicating an important role of p62 in enhancing these signaling pathways in the skin during AD-like inflammation.
Our results provide the first in vivo evidence for a pro-inflammatory role of p62 in skin and suggest that p62-dependent signaling pathways may be promising therapeutic targets to ameliorate the skin manifestations of AD and possibly psoriasis.

Copyright © 2021. Published by Elsevier Inc.