Atopic dermatitis (AD): protein called p62 influences the inflammatory changes in diseased epidermis


Frequently occurring chronic skin inflammation like in atopic dermatitis (AD or neurodermatitis) and psoriasis have different causes such as genetic predisposition, stress or allergens. These frequently occurring skin diseases are mostly attributed by biomedical scientists to a disturbed immune system, although the noticeable thickening and flaking of the epidermis, which is the outermost layer of skin, also indicates a disruption of the epithelial cells.

A team of researchers from the University Clinic for Dermatology and the Clinical Institute for Laboratory Medicine at MedUni Vienna has now been able to identify new molecular mechanisms as causes that could provide suitable starting points for new therapies.

Using patient samples and animal models, the researchers were able to show that a multifunctional protein called “p62” influences the inflammatory changes in diseased epidermis and that inhibiting p62 leads to an alleviation of chronic inflammation.

Sequestosome 1 / p62 is a multifunctional protein that affects the control of signal transduction and cellular balance (“homeostasis)” explains Erwin Wagner, head of the study from the University Clinic for Dermatology and the Clinical Institute for Laboratory Medicine at MedUni Vienna.

The present study therefore examined whether p62 plays a role in the development of atopic dermatitis (AD). Wagner: “For this purpose, AD-like skin lesions were induced by genetic inactivation of a certain gene, called JunB, in keratinocytes – this is the type of cell mainly found in the epidermis – which led to an increase in the expression of p62 in the skin of mice.” The contribution of p62 to pathological changes was then determined by the additional genetic inactivation of p62.

New therapy option for AD and related skin diseases

The result: The loss of p62 reduced skin damage, suggesting that the inhibition of p62-dependent signals could improve the clinical picture of atopic dermatitis (AD) and possibly also related skin diseases such as psoriasis. The researchers were also able to detect increased amounts of p62 in skin sections from patients with AD and psoriasis.

Further investigations showed that the inactivation of p62 normalized the altered differentiation of epidermal keratinocytes, reduced the thickening of the epidermis and decreased the infiltration of immune cells.

“Both the visible skin lesions were significantly reduced, as was the circulating immunoglobulin E (IgE) in the blood,” says Wagner, summarizing the results. High IgE levels are a typical characteristic of AD patients. At the molecular level, in turn, p62 activates certain signaling pathways that play a major role in inflammatory processes.

In the absence of p62 or by therapeutic blockade, these signaling pathways are not activated, which underlines the important role of p62 in AD-like inflammation.

Wagner: “These results provide the first in vivo evidence for an inflammatory role of p62 in the skin and suggest that p62-dependent signaling pathways are promising therapeutic targets for ameliorating the skin manifestations of AD and possibly also psoriasis.”

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, characterized by skin lesions, pruritic excoriations and susceptibility to cutaneous infections (1). There is no definitive cure for AD and the current treatment with immunosuppressive corticosteroid is associated with undesirable side effects.

Eosinophils (EOS), as the principal effector cells of allergic inflammation including AD (2), their accumulation and infiltration in tissues are mediated by the specific eosinophil chemokine eotaxin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin (2, 3).

IL-1 family cytokine IL-37/IL-1F7 can downregulate systemic and local inflammation and Th2 cytokines, by suppressing the production of pro-inflammatory mediators and cytokines in innate and adaptive immunity (4). Clinical studies have revealed that IL-37 levels in serum and skin tissue were significantly higher in AD patients compared with controls, thereby implicating the induction of IL-37 by skin barrier disruption (5).

IL-37 can be expressed by regulatory T cells (Treg) to enhance the expression of IL-10, Foxp3, and cytotoxic T-lymphocyte associated antigen-4 to promote the immunosuppressive activity of human Treg cells (6). Receptor IL-18Rα and IL-1R8 can mediate the multifaceted anti-inflammatory activity of IL-37, via the regulation of cellular adhesion and migration, and intracellular signal transduction mechanism (4, 7).

Among the five different IL-37 splice variants, IL-37b is the most effective and best characterized variant (8). This study was performed to investigate the anti-inflammatory mechanisms of IL-37 in AD by using recombinant human IL-37b and CRISPR/Cas9 human IL-37b knock-in mice.

IL-37 has been reported to alleviate inflammation by regulating intracellular AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling mechanism, which is the key regulator of autophagy (9). Autophagy has been extensively reported to play a vital role in regulating inflammation of the immune system (10).

It is the key player in resistance to bacterial, viral and protozoan infections (11) because the autophagy action mechanism can eliminate numerous unbeneficial microbes such as Streptococcus pyogenes (12). Gut microbiota (GM) can play a critical role in shaping the development of the host immune system in early life (13).

Early exposure to GM can foster the shift of Th1/Th2 balance to Th1 phenotype. In contrast, abnormal intestinal colonization in atopic diseases, especially in the development of the mucosal immune system, can shift the Th1/Th2 balance to Th2 response (14).

Th2 cell-derived cytokines such as IL-4, IL-5, and IL-13, induce the class switch of immunoglobulins to IgE, thereby mediating the allergic response. In addition, metabolites secreted by microbiota, e.g., short chain fatty acids such as butyrate, acetate and propionate, have been shown to control the differentiation and function of mucosal Tregs cells (15).

In the present study, the mechanism of detailed immunoregulatory role of IL-37b in Th2-related eosinophils-mediated interaction with dermal fibroblasts in AD was explored using in vitro and in vivo experiments. Further non-targeted metabolomic analysis and GM profile of CRISPR/Cas9 human IL-37b knock-in and wild type mice with AD were employed to elucidate the anti-inflammatory mechanism of IL-37 in AD.

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More information: Sequestosome 1/p62 enhances chronic skin inflammation. Journal of Allergy and Clinical


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