Abstract
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. We sought to 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 (JunBΔep). The contribution of p62 to pathological changes was determined by inactivation of p62 in JunBΔepp62-/- double knockout mice. Expression of p62 was elevated in skin lesions of JunBΔep mice, resembling upregulation of p62 in AD and psoriasis. When p62 was inactivated, JunBΔep-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 JunBΔep but not in JunBΔepp62-/- double knockout skin, indicating an important role of p62 in enhancing these signaling pathways in the skin during AD-like inflammation. Our results provide the first invivo 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.
Highlights
Because the pathological changes in JunBDep mice are induced by a genetic alteration of epidermal keratinocytes, this model resembles patients with atopic dermatitis (AD) associated with mutations in filaggrin, a gene expressed exclusively in keratinocytes,[11] but it displays features of AD subtypes with high IL-17, reminiscent of psoriasis.[4]
P62 is low in normal skin and expressed in psoriasis,[22] but was detected in all AD samples investigated (Fig 1, A; see this article’s Online Repository at www.jacionline.org), indicating that p62 might be involved in at least a subset of AD skin lesions
We investigated the mechanism by which p62 supports local skin lesions in the JunBDep mice. p62 enhances both NFkB and mechanistic target of rapamycin (mTOR) signaling[19] and independently acts as an adapter protein in autophagy
Summary
Atopic dermatitis (AD) is one of the most prevalent inflammatory skin diseases, but the signaling mechanisms initiating and maintaining skin lesions in AD are only partly understood.[1,2,3,4] Genetically engineered mouse models have proven useful to test the pathophysiological significance of potential regulators of skin inflammation.[5,6,7] We established Krt5-Cre–mediated deletion of the transcription factor JunB/AP-1 in epidermal keratinocytes (JunBDep) as an AD-like disease model, which involves Staphylococcus aureus growth, increased serum IgE as well as IL-6 and G-CSF–dependent inflammation in the face and ventral skin.[8,9,10] Because the pathological changes in JunBDep mice are induced by a genetic alteration of epidermal keratinocytes, this model resembles patients with AD associated with mutations in filaggrin, a gene expressed exclusively in keratinocytes,[11] but it displays features of AD subtypes with high IL-17, reminiscent of psoriasis.[4] JunB/AP-1 is a well-established regulator of cellular stress responses[12,13]; the mechanisms by which lack of epidermal JunB triggers inflammation are not fully known. Signaling through mechanistic target of rapamycin and natural factor kappa B was increased in JunBDep but not in JunBDep p622/2 double knockout skin, indicating an important role of p62 in enhancing
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