mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-4-617-632mimmun-1755Research ArticleОБЗОРЫREVIEWSРОЛЬ ХЕМОКИНОВОГО РЕЦЕПТОРА CXCR3 И ЕГО ЛИГАНДОВ ПРИ НЕКОТОРЫХ ИММУНОПАТОЛОГИЧЕСКИХ СОСТОЯНИЯХROLE OF CXCR3 CHEMOKINE RECEPTOR AND ITS LIGANDS IN CERTAIN DISEASESАрсентьеваН. А.ArsentievaN. A.

к.б.н., научный сотрудник лаборатории молекулярной иммунологии

197101, Россия, Санкт-Петербург, ул. Мира, 14

Тел.: 8 (904) 646-57-58

PhD (Biology), Research Associate, Laboratory of Molecular Immunology

14, ul. Mira, Saint-Petersburg, 197101, Russian Federation

arsentieva_n.a@bk.ruСеменовА. В.SemenovA. V.

д.б.н., заместитель директора по инновационной работе; профессор кафедры иммунологии 

197101,  Санкт-Петербург, ул. Мира, д. 14

197022, Санкт-Петербург, ул. Льва Толстого, д. 6-8

 

PhD, MD (Biology), Deputy Director for Innovations; Professor, Department of Immunology

14, ul. Mira, Saint-Petersburg, 197101, Russian Federation

6-8, L'va Tolstogo str.,  Saint- Petersburg, 197022, Russian Federation

alexvsemenov@yahoo.comЖебрунД. А.ZhebrunD. A.

к.б.н., научный сотрудник института молекулярной биологии и генетики

197341, Санкт-Петербург, ул. Аккуратова, д. 2

PhD (Biology), Research Associate, Institute of Molecular Biology and Genetics

2 Akkuratova str., Saint- Petersburg, 197341, Russian Federation

zhebrun@almazovcentre.ruВасильеваЕ. В.VasilyevaE. V.

к.б.н., аналитик 

115114, Москва, Шлюзовая набережная, 6с4

Ph.D., analyst 

 6с4 Shlyuzovaya emb., Moscow, 115114, Russian Federation

alenalenkina@gmail.comТотолянАрег А.TotolianAreg A.

д.м.н., профессор, академик РАН, директор; заведующий кафедрой иммунологии 

197101,  Санкт-Петербург, ул. Мира, д. 14

197022, Санкт-Петербург, ул. Льва Толстого, д. 6-8

 

PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, Director; Head, Department of Immunology

14, ul. Mira, Saint-Petersburg, 197101, Russian Federation

6-8, L'va Tolstogo str.,  Saint- Petersburg, 197022, Russian Federation

totolian@spbraaci.ruФБУН «Санкт-Петербургский научно-исследовательский институт эпидемиологии и микробиологии имени Пастера»РоссияSaint-Petersburg Pasteur Institute,Russian FederationФБУН «Санкт-Петербургский научно-исследовательский институт эпидемиологии и микробиологии имени Пастера», ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФРоссияSaint-Petersburg Pasteur Institute, Pavlov First Saint Petersburg State Medical UniversityRussian FederationФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Министерства здравоохранения РФRussian FederationNational Medical V. Almazov Research CentrRussian FederationBostongeneРоссияBostongeneRussian FederationФБУН «Санкт-Петербургский научно-исследовательский институт эпидемиологии и микробиологии имени Пастера», ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФRussian FederationSaint-Petersburg Pasteur Institute, Pavlov First Saint Petersburg State Medical UniversityRussian Federation201922082019214препринт617632Copyright © Арсентьева Н.А., Семенов А.В., Жебрун Д.А., Васильева Е.В., Тотолян А.А., 20192019Арсентьева Н.А., Семенов А.В., Жебрун Д.А., Васильева Е.В., Тотолян А.А.Arsentieva N.A., Semenov A.V., Zhebrun D.A., Vasilyeva E.V., Totolian A.A.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/1755

Хемокины представляют особое семейство цитокинов, основная функция которых состоит в контроле  миграции клеток, они служат ключевыми игроками в реакциях врожденного и адаптивного иммунного ответа. Направленный хемотаксис специфических субпопуляций лейкоцитов необходим не только для поддержания гомеостаза, а также в развитии иммунопатологических состояний, таких как рак, воспаление, инфекция, аллергия и аутоиммунные расстройства. Хемокины являются плейотропными молекулами, которые участвуют в физиологических и патофизиологических процессах. Например, хемокиновый рецептор CXCR3 экспрессируется на различных типах клеткок: активированных Т- и  В-лимфоцитах, натуральных киллерных клетках, эозинофилах и нейтрофилах, дендритных клетках, фибробластах, эндотелиальных и эпителиальных клетках, что обуславливает широкий спектр его функциональной активности. Рецептор CXCR3 представляет собой серпентиновый трансмембранный белок, в настоящее время известно три варианта CXCR3: CXCR3А, CXCR3В и CXCR3-alt. Лиганды рецептора CXCR3 включают IFNγ-зависимые хемокины: CXCL9, CXCL10, CXCL11 и хемокины, секретируемые тромбоцитами: CXCL4, CXCL4L1. Лиганды рецептора CXCR3 представляют собой отдельную группу ангиостатических хемокинов, поскольку для них характерно отсутствие аминокислотной последовательности Glu-Leu-Arg (ELR-мотива). IFNγ-зависимые лиганды рецептора CXCR3 являются провоспалительными хемокинами, они осуществляют свой хемотаксический потенциал за счет направленной миграции лимфоцитов, экспрессирующих CXCR3, к участкам воспаления, в основном они опосредуют хемотаксис активированных Т-клеток и их поляризацию. Молекулы хемокинов могут подвергаться пострансляционным модификациям, что оказывает влияние на их функции. Благодаря своей полифункциональности, лиганды CXCR3 играют важную роль в патогенезе многих заболеваний. В настоящем обзоре представлены данные о роли лигандов CXCR3 в иммунопатогенезе ряда заболеваний, в том числе результаты наших исследований хронического вирусного гепатита С, ревматоидного артрита и туберкулеза легких. Дополнительно, в статье обсуждается значимость хемокинов  как информативных биомаркеров, которые могут быть полезны для лабораторной диагностики различных иммунопатологических состояний. Этот обзор иллюстрирует универсальность IFNγ-зависимых хемокинов, как медиаторов иммунных реакций при различных заболеваниях. Исследование лигандов CXCR3, их изоформ и рецепторов, взаимодействий между собой и с рецепторами может внести существенный вклад в наше понимание в области сети хемокинов. Понимание системы IFNγ-зависимых хемокинов может иметь клиническое значение, как с точки зрения диагностики, так и с терапевтической точки зрения.

Chemokines are a special family of cytokines whose main function is to control cell migration; they are key players in the innate and adaptive immune responses. Directed chemotaxis of specific leukocyte subpopulations is necessary not only to maintain homeostasis, but also in development of some immunopathological conditions such as cancer, inflammation, infection, allergies and autoimmune disorders. Chemokines are pleiotropic molecules that are involved in physiological and pathophysiological processes. For example, the CXCR3 chemokine receptor is expressed on various cells: activated T and B lymphocytes, natural killers, eosinophils and neutrophils, dendritic cells, fibroblasts, endothelial and epithelial cells. Hence, CXCR3 and its ligands have a wide range of functional activity. CXCR3 ligands are the IFNγ-induced chemokines: CXCL9, CXCL10, CXCL11, and platelet-derived chemokines: CXCL4, CXCL4L1. All the CXCR3 ligands share common angiostatic properties due to lack of the Glu-Leu-Arg (ELR) motif. IFNγ-induced ligands of the CXCR3 are proinflammatory chemokines, they mainly recruit activated T cells and exert an effect on T cell polarization. Due to wide spectrum of biological activity, the ligands of CXCR3 receptor are involved in pathogenesis of various disorders, such as inflammation, infection, cancer, allergies and autoimmune disorders. In this review, we discuss the role of CXCR3 ligands in immunopathogenesis of various diseases, including the results of our studies in chronic hepatitis C, rheumatoid arthritis and pulmonary tuberculosis. Moreover, we have also discussed the potential laboratory diagnostic applicability of the chemokines in various diseases. This review illustrates a universal role of IFNγ-induced chemokines as mediators of immune responses in various diseases. The studies of CXCR3 ligands, their isoforms and receptors, interactions between themselves and with their receptors can provide a significant contribution to our understanding of the chemokine network. Understanding the system of IFNγ-dependent chemokines may have clinical implications, both for diagnostic tasks, and for therapeutic purposes.

хемокиныCXCR3IFNγ-зависимые лигандыгепатит Сревматоидный артриттуберкулезchemokinesCXCR3IFNγ-indused ligandshepatitis Crheumatoid arthritistuberculosisReferencesАрсентьева Н.А., Семенов А.В., Тотолян A.A. Роль полиморфизма генов цитокинов при вирусном гепатите С // Инфекция и иммунитет, 2012. T. 2, № 4. С. 687-698. doi: 10.15789/2220-7619-2012-4-687-698.Arsentieva N.A., Semenov A.V., Totolyan A.A. The role of cytokine gene polymorphism in viral hepatitis C. Infektsiya i immunitet = Russian Journal of Infection and Immunity, 2012, Vol. 2, no. 4, pp. 687-698. (In Russ.) doi: 10.15789/2220-7619-2012-4-687-698.Арсентьева Н.А., Кудрявцев И.В., Елезов Д.С., Семенов А.В., Эсауленко Е.В., Басина В.В., Тотолян А.А. Экспрессия хемокинового рецептора CXCR3 на субпопуляциях В-лимфоцитов периферической крови больных хроническим вирусным гепатитом С // Медицинская иммунология, 2013. T. 15, № 5. 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Анализ популяций Т-хелперных клеток памяти, экспрессирующих хемокиновые рецепторы CXCR3 и CCR6, в периферической крови больных хроническим вирусным гепатитом С // Бюллетень экспериментальной биологии и медицины, 2015. T. 160, № 8. C. 204-208.Elezov D.S., Kudryavtsev I.V., Arsentiev N.A., Basin V.V., Esaulenko E.V., Semenov A.V., Totolyan A.A. Analysis of populations T-helper memory cell expressing CXCR3 and CCR6 chemokine receptors in peripheral blood of patients with chronic viral hepatitis C. Byulleten eksperimentalnoy biologii i meditsiny = Bulletin of Experimental Biology and Medicine, 2015, Vol. 160, no. 8, pp. 204- 208. (In Russ.)Жебрун, Д.А., Маслянский А.Л., Титов А.Г., Патрухин А.П., Костарева А.А., Гольцева И.С, Тотолян A.A. Определение мРНК ангиогенных и ангиостатических хемокинов и их рецепторов в синовиальной оболочке методом количественной ПЦР в реальном времени // Медицинская иммунология, 2013. Т. 15, № 6. 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The authors declare that there are no conflicts of interest present.