The Role of Cytokines of Interleukin 36 Family in Immunopathogenesis of Psoriasis

Skin Health and Disease

Хайрутдинов

Самцов

et al. 2021

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Background Psoriasis is a chronic immune‐mediated inflammatory skin disease manifested by an increased rate of keratinocyte division. Currently, it has been established that the cytokines of the IL‐36 family play a significant role in the initiation and regulation of the inflammatory process in psoriasis. The IL‐36 cytokine found in skin is inactive and its activation requires proteolytic processing that may occur via the involvement of neutrophil serine proteases such as human neutrophil elastase (HNE). The localization of these enzymes in the upper layers of the epidermis suggests that topical application of HNE inhibitors could be efficacious in the treatment of psoriasis. Sivelestat is an HNE inhibitor developed for systemic use towards the treatment of acute respiratory failure. Aim The present study focussed on the investigation of the effects of sivelestat formulated for topical use, in the imiquimod‐induced model of psoriasis in mice. Methods The psoriasis‐like state was induced by application of imiquimod (Aldara ® ) 5% cream to mouse shaven skin. A group of 40 inbred mice of the BALB/c strain randomized into 4 groups of 10 was used in the experiment: Group 1 – no therapy (control), Group 2 – ointment (Vaseline) containing 1% sivelestat, Group 3 – cream (lanoline + olive oil + water in equal proportions) containing 1% sivelestat, Group 4 – 1% betamethasone dipropionate. Dermatological assessment of skin lesions was performed by means of the PASI method (mPASI), as well as histological and immunohistochemical evaluation. Results Based on the evaluation of efficacy manifestations, it was established that the total mPASI index value decreased by 50% during therapy with sivelestat cream and by 36% during therapy with sivelestat ointment. Histological study revealed that the epidermal thickness in groups that underwent therapy was 2.4–3.6 times lower compared to the control group. Immunohistochemical study of the skin indicated that following sivelestat treatment, the quantity of CD3+cells in the skin was 1.8–2.2 times lower, and the level of proliferative activity (Ki‐67+cells) was 2.3–2.9 lower compared to the non‐therapy group. In contrast to topical corticosteroids where the more pronounced anti‐inflammatory effect is typically seen with ointment formulations, with sivelestat we observed an opposite effect. The reasons for that reversal remain unclear. Conclusion Based on the results obtained using the animal model of imiquimod‐induced psoriasis, it was established that the HNE inhibitor sivelestat demonstrated efficacy comparable to that of a strong topical glucocorticoid steroidal drug (betamethasone dipropionate 1%). Significant resolution of skin lesions, reduction of epidermal thickness, diminishing of the skin infiltration with T‐lymphocytes and normalization of the cell division rate in epidermis and dermis were evident. ...

Section: Introductionmentioning

confidence: 99%

“…Genetic variations of this cytokine receptor are associated with the development of pustular forms of the disease 1 . Recent data also suggest a major role of IL‐36 in the pathogenesis of plaque psoriasis 2,3 …”

Section: Introductionmentioning

confidence: 99%

Preclinical efficacy investigation of human neutrophil elastase inhibitor sivelestat in animal model of psoriasis

Skin Health and Disease

Хайрутдинов

Самцов

et al. 2021

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Studying of the interleukin-36γ expression level in the skin of patients with plaque psoriasis

Pashkin

Пашкин²,

Vestnik dermatologii i venerologii

et al. 2019

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1 3-й военный госпиталь войск национальной гвардии Российской Федерации 192171, Российская Федерация, г. Санкт-Петербург, ул. Цимбалина, д. 36 2 Военно-медицинская академия им. С. М. Кирова Министерства обороны Российской Федерации 194044, Российская Федерация, г. Санкт-Петербург, ул. Академика Лебедева, д. 6 3 Санкт-Петербургский государственный технологический институт (технический университет) 190013, Российская Федерация, г. Санкт-Петербург, Московский просп., д. 26В настоящее время установлено, что цитокины семейства IL-36 занимают значимое место в инициации и регуляции воспалительного процесса при псориазе. Цель: изучение уровня экспрессии цитокинов IL-36γ в коже пациентов с бляшечным псориазом. Материал и методы. Исследовали биоптаты кожи 31 пациента с бляшечным псориазом. Группу сравнения составили по 20 биоптатов кожи больных ограниченным нейродермитом, нуммулярной экземой, красным плоским лишаем, грибовидным микозом (бляшечная стадия). В качестве группы контроля изучали биоптаты кожи 10 здоровых человек. Проведено иммуногистохимическое исследование кожи с использованием anti-IL-36γ антител. Результаты. Установлено увеличение относительной площади экспрессии IL-36γ в пораженной коже пациентов с бляшечным псориазом (7,4 %) по сравнению с непораженными участками (0,10 %) и группой контроля (0 %). Экспрессия IL-36γ в коже больных псориазом в прогрессирующем периоде (8,85 %) была в 1,42 раза выше, чем в стационарном периоде заболевания (6,2 %). Выявлена сильная прямая связь (r = 0,71) между уровнем экспрессии IL-36γ в пораженной коже и значением индекса PASI, умеренная прямая связь между уровнем экспрессии IL-36γ и толщиной эпидермиса (r = 0,34). В пораженной коже больных псориазом отмечалась выраженная экспрессия IL-36γ в верхних слоях эпидермиса, у пациентов группы сравнения (экзема, нейродермит, красный плоский лишай, грибовидный микоз) -слабая или умеренная, в непораженных участках кожи больных псориазом и здоровых людей -слабая или отсутствовала. Выводы. Установлено, что экспрессия IL-36γ в коже пациентов с бляшечным псориазом значительно выше, чем при других заболеваниях кожи. Полученные данные позволяют рассматривать этот цитокин в качестве возможного диагностического маркера и использовать его при проведении дифференциальной диагностики.Ключевые слова: бляшечный псориаз, ограниченный нейродермит, красный плоский лишай, нуммулярная экзема, грибовидный микоз, интерлейкин-36γ

The new external drug for the treatment of psoriasis based on inhibition of serine proteases

Vestnik dermatologii i venerologii

Сергеевич²,

Zharun

et al. 2021

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Background: Psoriasis is a chronic inflammatory immune-mediated disease characterized by an increased rate of keratinocyte division. The results of recent studies have made it possible to establish that the cytokines of the IL-36 family occupy a significant place in the initiation and regulation of the inflammatory process in psoriasis. IL-36 is in an inactive form and proteolytic processing is required for its activation in the skin, which is possible with the participation of neutrophilic serine proteases. Localization of these enzymes in the upper layers of the epidermis suggests the clinical efficacy of a topical targeted drug that inhibits serine proteases, sivelestat. On the basis of this active substance, we have created a drug in an external dosage form and conducted an experimental study of its effectiveness on a laboratory model of psoriasis. Aims: to evaluate the therapeutic efficacy of sivelestat in a laboratory model of imiquimod-induced psoriasis. Materials and methods: In the experiment, 40 inbred BALB/c mice were used, which were randomized into 4 groups of 10 each. An imiquimod-induced model of psoriasis was used. Mice of group No. I - without therapy (control), No. II - ointment (vaseline) containing 1% sivelestat, No. III - cream (lanolin + olive oil + water in equal proportions) containing 1% sivelestat, No. IV - betamethasone cream dipropionate 0.05%. Clinical assessment of skin rashes was performed using the PASI-modified method (mPASI), as well as histological and immunohistochemical examination of the skin. Results: When evaluating clinical manifestations, it was found that the total mPASI index when using sivelestat cream decreased by 50%, and sivelestat ointment - by 36%. The histological examination showed that the thickness of the epidermis in the groups where the therapy was applied was 2.4-3.6 times less than in the control group. An immunohistochemical study of the skin found that after treatment with sivelestat, the number of CD3 + cells in the skin was 1.8-2.2 times less, and the level of proliferative activity (Ki-67 + cells) was 2.3-2.9 times less. lower than in the group without therapy Conclusions: On a laboratory model of imiquimod-induced psoriasis, it was found that a serine protease inhibitor (sivelestat) has a therapeutic efficacy comparable to a strong topical glucocorticosteroid drug (betamethasone dipropionate 0.05%). A pronounced resolution of the elements of the skin rash, a reduction in the thickness of the epidermis, a decrease in skin infiltration with T-lymphocytes and a normalization of the rate of cell division of the epidermis and dermis are shown. Suppression of the activity of IL-36-mediated inflammation in the skin by means of topical inhibitors of serine proteases is a promising new direction in the treatment of patients with psoriasis.