mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-IFA-1880mimmun-1880Research ArticleОБЗОРЫREVIEWSСемейство интерлейкина-36 как новый регулятор воспалительного ответа в барьерных тканяхInterleukin-36 family as a novel regulator of inflammation in the barrier tissuesСенниковаС. В.SennikovaS. V.

Сенникова С.В. – аспирант лаборатории цитокинов

125212, Москва, ул. Адмирала Макарова, 10.

Sennikova S.V., Postgraduate Student, Laboratory of Cytokines

125212, Moscow, Admiral Makarov str., 10.

drsennikova@mail.ruТоптыгинаА. П.ToptyginaA. P.

Топтыгина А.П. – д.м.н., ведущий научный сотрудник лаборатории цитокинов; профессор кафедры иммунологии биологического факультета

125212, Москва, ул. Адмирала Макарова, 10.

Toptygina A.P., PhD, MD (Medicine), Leading Research Associate, Laboratory of Cytokines; Professor, Department of Immunology, Faculty of Biology

125212, Moscow, Admiral Makarov str., 10.

toptyginaanna@rambler.ruФБУН «Московский научно-исследовательский институт эпидемиологии и микробиологии имени Г.Н. Габричевского» РоспотребнадзораРоссияG.N.Gabrichevsky Research Institute for Epidemiology and MicrobiologyRussian FederationФБУН «Московский научно-исследовательский институт эпидемиологии и микробиологии имени Г.Н. Габричевского» Роспотребнадзора; ФГБОУ ВО «Московский государственный университет имени М.В. Ломоносова»РоссияG.N.Gabrichevsky Research Institute for Epidemiology and Microbiology; M. Lomonosov Moscow State UniversityRussian Federation2020290120202214960Copyright © Сенникова С.В., Топтыгина А.П., 20202020Сенникова С.В., Топтыгина А.П.Sennikova S.V., Toptygina A.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1880

В составе суперсемейства интерлейкина-1 (IL-1) десять лет назад было выделено семейство интерлейкина-36 (IL-36). Данное семейство включает три изоформы IL-36α, IL-36β, IL-36γ, обладающие провоспалительной активностью, и рецепторный антагонист – IL-36ra, реализующий противовоспалительную функцию. Все они связываются с одним и тем же рецептором IL-1R6. Провоспалительные изоформы вовлекают в сигналинг также добавочный белок IL-1RAcP, в результате образовавшийся рецепторный гетеродимер проводит сигнал внутрь клетки. IL-36ra, напротив, препятствует образованию гетеродимера и блокирует прохождение сигнала. Цитокины семейства IL-36 и рецепторы к нему экспрессируются в норме на эпителиальных клетках барьерных тканей, таких как респираторный, кишечный тракт и кожа. Как и все цитокины суперсемейства IL-1, IL-36 синтезируется в неактивной форме и требует активации, но не за счет каспаз, а за счет ферментов нейтрофилов, таких как катепсин G, протеиназа-3 и эластаза, которые постоянно присутствуют в барьерных тканях. В связи с этим IL-36 вовлечен в гомеостаз барьерных тканей. По-видимому, система цитокинов IL-36 появилась в ответ на развившуюся способность некоторых микроорганизмов ускользать от распознавания и активации системы врожденного иммунитета, в частности провоспалительной системы IL-1. Нарушение баланса между провоспалительными и противовоспалительными ветвями легко приводит к воспалению соответствующей ткани. В данном обзоре рассмотрено участие цитокинов семейства IL-36 в гомеостазе барьерных тканей, роль семейства IL-36 в патогенезе бактериальных, вирусных и грибковых заболеваний кожи, атопического дерматита, аутоиммунных заболеваний, таких как ревматоидный артрит, системная красная волчанка, синдром Шегрена, язвенный колит и болезнь Крона. Наиболее хорошо изучена роль цитокинов семейства IL-36 в иммунопатогенезе псориаза. В настоящем обзоре изложены современные представления об иммунопатогенезе псориаза. Показана особая роль цитокинов семейства IL-36 как в индукции псориатического воспаления, так и в формировании петли положительной обратной связи, поддерживающей и усиливающей иммунный компонент воспаления, что приводит к прогрессированию заболевания. Отдельно обсуждаются современные методы лечения псориаза, в частности возможный перспективный подход к блокаде IL-36 или использование рекомбинантного IL-36ra для лечения псориатических больных. Экспериментальные исследования в этой области на мышах дают основание для оптимизма.

The interleukin-36 (IL-36) family was discerned in the superfamily of interleukin-1 (IL-1) ten years ago. This family includes three isoforms of IL-36α, IL-36β, IL-36γ, which have pro-inflammatory activity and a specific receptor antagonist, IL-36ra, which implements anti-inflammatory function. All of them bind to the same IL-1R6 receptor. The pro-inflammatory isoforms also involve an accessory IL-1RAcP protein into signaling; resulting into conduction of a signal into the cell via the assembling heterodimer receptor. In contrast, IL-36ra inhibits the formation of a heterodimer and blocks the signal transmission. The cytokines of the IL-36 family and appropriate receptors are normally expressed on epithelial cells in barrier tissues such as the respiratory, intestinal tract and skin. Like all cytokines of the IL-1 superfamily, IL-36 is synthesized as inactive form and requires activation, but not due to caspases, but being mediated by neutrophil enzymes, such as cathepsin G, proteinase-3, and elastase, which are constantly present in barrier tissues. In this regard, IL-36 is involved in homeostasis of barrier tissues. Apparently, the IL-36 cytokine system appeared in response to the developing ability of some microorganisms to avoid immune recognition and activation of innate immune response, and, in particular, the IL-1 pro-inflammatory system. An imbalance between the pro- and anti-inflammatory pathways readily causes inflammation in the corresponding tissue. This review discusses participation of cytokines from the IL-36 family in homeostasis of barrier tissues, as well as potential role of the IL-36 family in pathogenesis of bacterial, viral, and fungal skin diseases, atopic dermatitis, autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, ulcerative colitis and Crohn's disease. The role of IL-36 family cytokines in the immunopathogenesis of psoriasis has been well studied. This review is presenting the modern ideas about immune pathogenesis of psoriasis. The special role of cytokines from the IL-36 family was shown both for induction of psoriatic inflammation and evolving a positive feedback loop that supports and enhances the immune component of inflammation, which leads to progression of the disease. Moreover, modern methods of treating psoriasis are discussed, in particular, a possible promising approach to IL-36 blockade, or usage of recombinant IL-36ra for the treatment of psoriatic patients. Experimental studies in this area in mice provide some grounds for optimism.

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The authors declare that there are no conflicts of interest present.