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^Δep). The contribution of p62 to pathological changes was determined by inactivation of p62 in JunB^Δep p62^−/− double knockout mice.

Results

Expression of p62 was elevated in skin lesions of JunB^Δep mice, resembling upregulation of p62 in AD and psoriasis. When p62 was inactivated, JunB^Δep-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^Δep but not in JunB^Δep 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.