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Mature interleukin-36γ induces stratum corneum exfoliation in generalized pustular psoriasis by suppressing corneodesmosin

ABSTRACT: Loss-of-function mutations in the IL36RN gene encoding IL-36 receptor antagonist (IL-36RA) cause familial generalized pustular psoriasis (GPP), which sometimes begins shortly after birth and is difficult to treat, and its effects on the epidermis are unclear. This study aimed to investigate the involvement of IL-36 receptor agonists in the epidermal formation of GPP. In this study, we found that IL-36 receptor agonists, especially mature IL-36γ, stimulate IL-8 and proIL-36γ production in the epidermis, while down-regulating the genes encoding epidermal cornified envelope-related proteins such as corneodesmosin. IL-36 receptor antagonists and monoclonal anti-IL-36γ antibodies counteract the effect of mature IL-36γ on corneodesmosin in keratinocytes in a dose-dependent manner. In the epidermis of generalized pustular psoriasis patients with IL36RN loss-of-function mutations, proIL-36γ is overproduced in the epidermis and corneodesmosin protein expression is markedly decreased in the region of giant subcorneal pustules called Kogoj’s spongiform pustules with high neutrophil infiltration. IL-8 induced by mature IL-36γ induces several neutrophils in the epidermis, and the newly produced proIL-36γ is cleaved to the mature form by neutrophil proteases. This newly produced mature IL-36γ was predicted to further suppress the gene expression of the granulosa-stratum-associated protein, corneodesmosin, leading to significant stratum corneum exfoliation and formation of giant subcorneal pustules. Overall, our results elucidate the mechanism underlying the formation of Kogoj’s spongiform pustules in generalized pustular psoriasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235635 | GEO | 2023/11/09

REPOSITORIES: GEO

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Project description:Transcriptional profiling of Homo sapiens inflammatory skin diseases (whole skin biospies): Psoriasis (Pso), vs Atopic Dermatitis (AD) vs Lichen planus (Li), vs Contact Eczema (KE), vs Healthy control (KO) In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/TNFα-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, due to its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation. In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/TNFα-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, due to its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation.

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Mature interleukin-36γ induces stratum corneum exfoliation in generalized pustular psoriasis by suppressing corneodesmosin

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