Sequestosome 1/p62 enhances chronic skin inflammation

Background: 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 proinflammatory and mechanistic target of rapamycin signaling. Objective: We sought to determine whether p62 plays a role in the cutaneous and systemic manifestations of an AD-like mouse model. Methods: AD-like skin lesions were induced by deletion of JunB/AP-1, specifically in epidermal keratinocytes (JunB(Delta ep)). The contribution of p62 to pathological changes was determined by inactivation of p62 in JunB(Delta ep) p62(-/-) double knockout mice. Results: Expression of p62 was elevated in skin lesions of JunB(Delta ep) mice, resembling upregulation of p62 in AD and psoriasis. When p62 was inactivated, JunB(Delta ep)-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 mechanistic target of rapamycin and natural factor kappa B was increased in JunB(Delta ep) but not in JunB(Delta ep) p62(-/-) double knockout skin, indicating an important role of p62 in enhancing these signaling pathways in the skin during AD-like inflammation. Conclusions: Our results provide the first in vivo evidence for a proinflammatory 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.

Automated summary

The activation of p62 is associated with skin lesions in an AD-like mouse model, and inactivation of p62 significantly reduces defects in keratinocyte differentiation, epidermal thickening, skin infiltration by immune cells, and the development of macroscopic skin lesions in the model.