mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2018-2-163-170mimmun-1478Research ArticleОБЗОРЫREVIEWSРОЛЬ ЦИТОКИНОВ СЕМЕЙСТВА ИНТЕРЛЕЙКИНА-36 В ИММУНОПАТОГЕНЕЗЕ ПСОРИАЗАTHE ROLE OF CYTOKINES OF INTERLEUKIN 36 FAMILY IN IMMUNOPATHOGENESIS OF PSORIASISПашкинА. Ю.PashkinA. Yu.

клинический ординатор кафедры кожных и венерических болезней 

194044, Россия, Санкт-Петербург, ул. Академика Лебедева, 6. Тел.: 8 (911) 091-83-73

Clinical Resident, Department of Dermatology and Venerology

194044, Russian Federation, St. Petersburg, Acad. Lebedev str., 6. Phone: 7 (911) 091-83-73

alek-pashkin@yandex.ruВоробьеваЕ. И.VorobyevaE. I.

инженер НИЛ «Клеточная биотехнология»

Engineer, Research Laboratory “Cell Biotechnology”

ХайрутдиновВ. Р.KhairutdinovV. R.

д.м.н., доцент кафедры кожных и венерических болезней

PhD, MD (Medicine), Associate Professor, Department of Dermatology and Venerology

БелоусоваИ. Э.BelousovaI. E.

д.м.н., профессор кафедры кожных и венерических болезней

PhD, MD (Medicine), Professor, Department of Dermatology and Venerology

СамцовА. В.SamtsovA. V.

д.м.н., профессор, заведующий кафедрой кожных и венерических болезней

PhD, MD (Medicine), Professor, Head, Department of Dermatology and Venerology

ГарабаджиуА. В.GarabagiouA. V.

д.х.н., проректор по научной работе

PhD, MD (Chemistry), Vice-Rector for Research 

ФГБВОУ ВО «Военно-медицинская академия имени С.М. Кирова» Министерства образования РФРоссияS.M. Kirov Military Medical AcademyRussian FederationФГБОУ ВО «Санкт-Петербургский государственный технологический институт (технический университет)»РоссияSt. Petersburg State Technological Institute (Technical University)Russian Federation201815032018202163170Copyright © Пашкин А.Ю., Воробьева Е.И., Хайрутдинов В.Р., Белоусова И.Э., Самцов А.В., Гарабаджиу А.В., 20182018Пашкин А.Ю., Воробьева Е.И., Хайрутдинов В.Р., Белоусова И.Э., Самцов А.В., Гарабаджиу А.В.Pashkin A.Y., Vorobyeva E.I., Khairutdinov V.R., Belousova I.E., Samtsov A.V., Garabagiou A.V.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/1478

В последнее десятилетие значительно расширились представления об иммунных механизмах развития псориаза. В данном обзоре описаны биологические свойства цитокинов семейства интерлейкина-36 (IL-36) и их роль в патогенезе бляшечного псориаза, генерализованного пустулезного псориаза и псориатического артрита. Кератиноциты и дендритные клетки являются основными источниками IL-36 в коже. Продукция данного цитокина многократно усиливается при воспалении. Проведенные исследования показали, что в пораженной коже больных псориазом наблюдается повышенная экспрессия IL-36α и IL-36γ. IL-36γ можно рассматривать в качестве специфического маркера псориаза, который не встречается при других воспалительных заболеваниях кожи (нейродермит, красный плоский лишай, экзема). Уровень этого цитокина коррелирует с тяжестью псориаза и снижается после анти-TNFα-терапии. Высокий уровень цитокинов IL-36 в области псориатических высыпаний коррелирует с повышенной концентрацией в коже провоспалительных TNFα, IL-17, IL-22 и IFNγ. Приведены литературные данные о роли мутациии гена IL-36RN, кодирующего антагонист рецептора IL-36ra, в развитии генерализованного пустулезного псориаза (ГПП). Избыточная активность агонистов IL-36, приводящая к накоплению нейтрофильных гранулоцитов в эпидермисе, может быть ключевым событием в патогенезе ГПП. В статье отражены современные представления о роли нейтрофильных гранулоцитов в развитии хронических воспалительных процессов, лежащих в основе патогенеза псориаза. Протеазы нейтрофилов катепсин G, эластаза и протеиназа-3 являются мощными IL-36-активирующими ферментами, повышающими активность цитокинов IL-36 до 500 раз. В данном обзоре описан новый механизм участия нейтрофилов в иммунном ответе – нетоз. Во время нетоза во внеклеточное пространство выделяется большое количество цитокинов, антимикробных пептидов, внутриклеточных компонентов, сериновых протеаз, которые могут быть вовлечены в инициирование и поддержание хронического воспалительного процесса при псориазе.

Появление сведений о роли новых цитокинов семейства IL-36 в качестве одних из основных медиаторов псориаза открыло новые терапевтические цели для лечения этого заболевания и разработки новых методов таргетной терапии. Специфическое блокирование передачи сигналов IL-36R или ингибирование нейтрофильных протеаз катепсина G, нейтрофильной эластазы, осуществляющих активацию членов семейства IL-36, вероятно, будет успешной стратегией в терапии псориаза. 

Over last decade, the importance of immune mechanisms for development of psoriasis has expanded considerably. This review describes biological properties of the cytokines from the interleukin-36 (IL-36) family, and their role in pathogenesis of plaque psoriasis, generalized pustular psoriasis and psoriatic arthritis. Keratinocytes and dendritic cells (DC) are the main sources of IL-36 in the skin. Production of this cytokine is greatly enhanced by inflammation. The studies have shown that, in affected skin of psoriatic patients, an increased expression of IL-36α and IL-36γ is observed. IL-36γ can be considered a specific marker of psoriasis, which is not found in other inflammatory skin diseases (neurodermatitis, lichen planus, eczema). The levels of this cytokine correlate with severity of psoriasis and decreases after anti-TNFα therapy. High level of IL-36 cytokines in the areas of psoriatic eruptions correlates with increased concentrations of pro-inflammatory TNFα, IL-17, IL-22 and IFNγ in the skin. We present literature data on the role of IL-36RN mutation which encodes the IL-36ra receptor antagonist, playing a role in the development of generalized pustular psoriasis (GPP). Excessive activity of IL-36 agonists leading to accumulation of neutrophilic granulocytes in epidermis may be a key event in the GPP pathogenesis. The article deals with modern ideas about the role of neutrophilic granulocytes in development of chronic inflammatory processes underlying pathogenesis of psoriasis. Proteases of neutrophils (cathepsin G, elastase and proteinase-3) are potent IL-36 activating enzymes that increase activity of IL-36 cytokines up to 500 times. In this review, a new mechanism (netosis) is suggested for the role of neutrophils in immune response. During the netosis, a large number of cytokines, antimicrobial peptides, intracellular components, serine proteases are released into the extracellular space. Thus, they may be involved into initiation and maintenance of a chronic inflammatory process in psoriasis.

The present information concerning a role of new IL-36 family cytokines as one of the main psoriasis mediators has opened new therapeutic goals for the treatment of this disease and development of new methods of targeted therapy. Specific blocking of IL-36R signaling, or inhibition of neutrophil proteases of cathepsin G, neutrophil elastase that activate members of the IL-36 family, is likely to be a successful strategy in the therapy of psoriasis. 

псориазиммунный ответинтерлейкины семейства IL-36нейтрофильные гранулоцитынейтрофильные внеклеточные ловушкисериновые протеазыpsoriasisimmune responseIL-36 family interleukinsneutrophilic granulocytesneutrophilic extracellular trapsserine proteasesРабота выполнена при поддержке гранта Минобрнауки № 14.В25.31.0013.ReferencesКоротина О.Л., Генералов И.И. Нейтрофильные внеклеточные ловушки: механизмы образования, функции // Иммунопатология, аллергология, инфектология, 2012. № 4. С. 23-32. [Korotina O.L., Generalov I.I. Neutrophil extracellular traps: mechanisms of formation, functions. Immunopatologiya, Allergologiya, Infektologiya = International Journal of Immunopathology, Allergology, Infectology, 2012, no. 4, pp. 23-32. (In Russ.)]Коротина О.Л., Генералов И.И. Нейтрофильные внеклеточные ловушки: механизмы образования, функции // Иммунопатология, аллергология, инфектология, 2012. № 4. С. 23-32. [Korotina O.L., Generalov I.I. 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The authors declare that there are no conflicts of interest present.