Epigenetic factors involved in the pathophysiology of inflammatory skin diseases

Möbus, Lena; Weidinger, Stephan; Emmert, Hila

doi:10.1016/j.jaci.2019.10.015

Cited by 22 publications

(18 citation statements)

References 101 publications

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“…AD is a complex disease whose etiology has not yet been fully deciphered due to its heterogeneity resulting from patient age, ethnicity, and lifestyle factors [7][8][9]. Moreover, although a genetic predisposition is undeniable in AD pathogenesis, the relative contribution of (epi)genetic [10][11][12][13] versus environmental factors [14][15][16] remains unknown. Heterogeneity of AD due to genetic polymorphism extends beyond filaggrin (FLG) loss-of-function mutations, since patients with serine peptidase inhibitor Kazal-type 5 (SPINK5) mutations also exhibit a severe AD-like phenotype, as do other patients with inherited disorders [17,18].…”

Section: Atopic Dermatitismentioning

confidence: 99%

Atopic Dermatitis: The Fate of the Fat

Pavel

Blunder

Moosbrugger‐Martinz

et al. 2022

IJMS

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Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component, as children from parents with AD have a twofold increased chance of developing the disease. Genetic risk loci and epigenetic modifications reported in AD mainly locate to genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors since environmental triggers such as stress, pollution, microbiota, climate, and allergens also play a crucial role. Alterations of the epidermal barrier in AD, observed at all stages of the disease and which precede the development of overt skin inflammation, manifest as: dry skin; epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system; and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, such as ceramides and free fatty acids. Thus, a compelling question is whether AD is primarily a lipid disorder evolving into a chronic inflammatory disease due to genetic susceptibility loci in immunogenic genes. In this review, we focus on lipid abnormalities observed in the epidermis and blood of AD patients and evaluate their primary role in eliciting an inflammatory response.

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Section: Atopic Dermatitismentioning

confidence: 99%

Atopic Dermatitis: The Fate of the Fat

Pavel

Blunder

Moosbrugger‐Martinz

et al. 2022

IJMS

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“…We hypothesized that GADD45 molecules could play a role in the development of psoriasis, a disease where the interaction of keratinocytes and immune cells is pivotal, and where epigenetic modifications cause aberrant increases in epidermal thickness, keratinocyte differentiation, proliferation and inflammation 16 .…”

Section: Introductionmentioning

confidence: 99%

Growth arrest and DNA damage-inducible proteins (GADD45) in psoriasis

Rodríguez‐Jiménez

Fernández-Messina

Ovejero‐Benito

et al. 2021

Sci Rep

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The interplay between T cells, dendritic cells and keratinocytes is crucial for the development and maintenance of inflammation in psoriasis. GADD45 proteins mediate DNA repair in different cells including keratinocytes. In the immune system, GADD45a and GADD45b regulate the function and activation of both T lymphocytes and dendritic cells and GADD45a links DNA repair and epigenetic regulation through its demethylase activity. Here, we analyzed the expression of GADD45a and GADD45b in the skin, dendritic cells and circulating T cells in a cohort of psoriasis patients and their regulation by inflammatory signals. Thirty patients (17 male/13 female) with plaque psoriasis and 15 controls subjects (7 male/8 female), were enrolled. Psoriasis patients exhibited a lower expression of GADD45a at the epidermis but a higher expression in dermal infiltrating T cells in lesional skin. The expression of GADD45a and GADD45b was also higher in peripheral T cells from psoriasis patients, although no differences were observed in p38 activation. The expression and methylation state of the GADD45a target UCHL1 were evaluated, revealing a hypermethylation of its promoter in lesional skin compared to controls. Furthermore, reduced levels of GADD45a correlated with a lower expression UCHL1 in lesional skin. We propose that the demethylase function of GADD45a may account for its pleiotropic effects, and the complex and heterogeneous pattern of expression observed in psoriatic disease.

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“…The epigenetic landscape in AD is relatively less explored, although it shares some similarities with psoriasis. 51 Research thus far has demonstrated widespread methylation events in AD lesional skin compared with healthy skin. 52 Recently, alterations in DNA methylation were also found in the skin homing CD4 + cell of AD patients.…”

Section: Epigeneticmodificationsinatopicdermatitismentioning

confidence: 99%

Epigenetic‐modifying therapies: An emerging avenue for the treatment of inflammatory skin diseases

McGee

2021

Experimental Dermatology

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Epigenetic modifications include DNA methylation, histone modification and the action of microRNAs. These mechanisms coordinate in complex networks to control gene expression, thereby regulating key physiological processes in the skin and immune system. Recently, researchers have turned to the epigenome to understand the pathogenesis of inflammatory skin diseases. In psoriasis and atopic dermatitis, epigenetic modifications contribute to key pathogenic events such as immune activation, T-cell polarization and keratinocyte dysfunction. These discoveries have introduced new possibilities for the treatment of skin diseases; unlike genetics, epigenetic alterations are readily modifiable and potentially reversible. In this viewpoint essay, we summarize the current state of epigenetic research in inflammatory skin diseases and propose that targeting the histone machinery is a promising avenue for the development of new therapies for psoriasis and atopic dermatitis. Expanding on the progress that has already been made in the field of cancer epigenetics, we discuss existing epigenetic-modifying tools that can be applied to the treatment of inflammatory skin diseases and consider future directions for investigation in order to allow for the widespread clinical application of such therapies.

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Epigenetic factors involved in the pathophysiology of inflammatory skin diseases

Cited by 22 publications

References 101 publications

Atopic Dermatitis: The Fate of the Fat

Atopic Dermatitis: The Fate of the Fat

Growth arrest and DNA damage-inducible proteins (GADD45) in psoriasis

Epigenetic‐modifying therapies: An emerging avenue for the treatment of inflammatory skin diseases

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