| First Author | Sukseree S | Year | 2021 |
| Journal | J Allergy Clin Immunol | Volume | 147 |
| Issue | 6 | Pages | 2386-2393.e4 |
| PubMed ID | 33675820 | Mgi Jnum | J:329701 |
| Mgi Id | MGI:6824391 | Doi | 10.1016/j.jaci.2021.02.028 |
| Citation | Sukseree S, et al. (2021) Sequestosome 1/p62 enhances chronic skin inflammation. J Allergy Clin Immunol 147(6):2386-2393.e4 |
| abstractText | 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(Deltaep)). The contribution of p62 to pathological changes was determined by inactivation of p62 in JunB(Deltaep)p62(-/-) double knockout mice. RESULTS: Expression of p62 was elevated in skin lesions of JunB(Deltaep) mice, resembling upregulation of p62 in AD and psoriasis. When p62 was inactivated, JunB(Deltaep)-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(Deltaep) but not in JunB(Deltaep)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. |
