mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-IAM-2037mimmun-2037Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESВзаимосвязь фенотипа и метаболизма нейтрофилов крови у больных раком почкиImmunophenotype and metabolism are linked in peripheral blood neutrophils from patients with kidney cancerСавченкоА. А.SavchenkoA. A.

Савченко Андрей Анатольевич – доктор медицинских наук, профессор, руководитель лаборатории клеточно-молекулярной физиологии и патологии

Красноярск

Savchenko Andrei A., PhD, MD (Medicine), Professor, Head, Laboratory of Molecular and Cellular Physiology and Pathology

Krasnoyarsk

aasavchenko@yandex.ruБорисовА. Г.BorisovA. G.

Борисов Александр Геннадьевич – кандидат медицинских наук, ведущий научный сотрудник лаборатории клеточно-молекулярной физиологии и патологии

Красноярск

Borisov Alexandr G., PhD (Medicine), Leading Research Associate, Laboratory of Molecular and Cellular Physiology and Pathology

Krasnoyarsk

2410454@mail.ruКудрявцевИ. В.KudryavtsevI. V.

Кудрявцев Игорь Владимирович – кандидат биологических наук, старший научный сотрудник отдела иммунологии ФГБНУ «Институт экспериментальной медицины»; доцент кафедры иммунологии ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФ

197376, Санкт-Петербург, ул. Акад. Павлова, 12

Kudryavtsev Igor V., PhD (Biology), Senior Research Associate, Department of Immunology, Institute of Experimental Medicine; Associate Professor, Department of Immunology, First St. Petersburg State I. Pavlov Medical University

197376, St. Petersburg, Acad. Pavlov str., 12

igorek1981@yandex.ruГвоздевИ. И.GvozdevI. I.

Гвоздев Иван Игоревич – младший научный сотрудник лаборатории клеточно-молекулярной физиологии и патологии

Красноярск

Gvozdev Ivan I., Junior Research Associate, Laboratory of Molecular and Cellular Physiology and Pathology

Krasnoyarsk

dyh.88@mail.ruМошевА. В.MoshevA. V.

Мошев Антон Викторович – младший научный сотрудник лаборатории клеточно-молекулярной физиологии и патологии

Красноярск

Moshev Anton V., Junior Research Associate, Laboratory of Molecular and Cellular Physiology and Pathology

Krasnoyarsk

kinger1@mail2000.ruНаучно-исследовательский институт медицинских проблем Севера – обособленное подразделение ФГБНУ «Федеральный исследовательский центр „Красноярский научный центр Сибирского отделения Российской академии наук“»РоссияResearch Institute of Medical Problems of the North, Krasnoyarsk Science Center, Siberian Branch, Russian Academy of SciencesRussian FederationФГБНУ "Институт экспериментальной медицины"; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФРоссияInstitute of Experimental Medicine; First St. Petersburg State I. Pavlov Medical UniversityRussian Federation202027112020225887896Copyright © Савченко А.А., Борисов А.Г., Кудрявцев И.В., Гвоздев И.И., Мошев А.В., 20202020Савченко А.А., Борисов А.Г., Кудрявцев И.В., Гвоздев И.И., Мошев А.В.Savchenko A.A., Borisov A.G., Kudryavtsev I.V., Gvozdev I.I., Moshev 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/2037

Целью исследования было изучение особенностей взаимосвязи между экспрессией рецепторов активации и адгезии нейтрофилов крови и внутриклеточной активностью ферментов у больных раком почки (РП). Больные (n = 72) с РП (T3N0M0, светлоклеточный тип) были обследованы до хирургического лечения на базе Красноярского краевого онкологического диспансера. Диагноз «РП» подтвержден гистологически. Фенотип нейтрофилов крови изучали методом проточной цитометрии. Уровни экспрессии поверхностных рецепторов нейтрофилов оценивали по средней интенсивности флуоресценции. Активность НАД- и НАДФ-зависимых дегидрогеназ в нейтрофилах крови измеряли биолюминесцентным методом. Установлено, что изменение фенотипа нейтрофилов крови у больных с РП проявляется на фоне торможения основных внутриклеточных метаболических процессов и во взаимосвязи с ними. Особенностями фенотипического состава нейтрофилов у больных с РП было уменьшение относительного количества клеток, экспрессирующих адгезивные (CD11b и CD62L) и функциональные (CD64 и HLA-DR) рецепторы. Нейтрофилы крови больных раком интенсивнее экспрессировали такие молекулы, как CD11b, CD16 и HLA-DR. Эти изменения в фенотипе нейтрофилов крови у больных с РП определялись на фоне выраженного уменьшения количества незрелых клеток. Метаболические особенности цитоплазматического компартмента нейтрофилов крови у больных с РП характеризовались снижением активности глюкозо-6-фосфатдегидрогеназы (ключевого и инициализирующего фермента пентозофосфатного цикла) и NADH-зависимой реакцией лактатдегидрогеназы (НАДН-ЛДГ, анаэробный гликолиз). Митохондриальный метаболизм у нейтрофилов больных с РП характеризовался разнонаправленными изменениями активности НАД- (НАДН-ГДГ) и НАДФ-зависимых глутаматдегидрогеназ (снижение активности НАД-зависимых и повышение активности НАДФ-зависимых) и снижением активности НАДН-зависимая реакция малатдегидрогеназы. Установленные особенности в активности митохондриальных ферментов характеризуют нарушение НАД-зависимых процессов, что может привести к снижению интенсивности аэробных энергетических процессов. С помощью корреляционного анализа было обнаружено, что особенности взаимосвязей у больных РП определялись отрицательным влиянием активности НАДНГДГ и НАДН-ЛДГ на уровни экспрессии рецепторов активации и адгезии нейтрофилов. Только активность глутатионредуктазы в нейтрофилах больных РП положительно коррелировала с экспрессией молекул CD23 и HLA-DR. Повышение активности энергетических процессов (в том числе процессов взаимодействия цикла трикарбоновых кислот с реакциями обмена аминокислот) в нейтрофилах крови больных раком почки может стимулировать уровни экспрессии рецепторов активации и адгезии и повышать противоопухолевую активность нейтрофилов.

The aim of the present study was to analyze the relationships between expression of activation and adhesion receptors on peripheral blood neutrophils, and intracellular activity of some neutrophil enzymes in patients with kidney cancer (KC). Patients and methods: the KC patients (n = 72) (T3N0M0, clear-cell type) were examined prior to surgical treatment at the Krasnoyarsk Regional Oncology Center. The diagnosis was verified histologically for all KC patients. The phenotype of blood neutrophils was studied using flow cytometry. The surface receptor expression levels of the neutrophils were evaluated by mean fluorescence intensity. NAD and NADP-dependent dehydrogenases activities in purified peripheral blood neutrophils were measured by bioluminescent method. Results: we have found that the phenotypic alterations in circulating KC patients’ neutrophils appeared along with inhibition of main intracellular metabolic processes and were closely linked with them. The features of the phenotypic imbalance in the neutrophils from KC patients were associated with a decrease in blood cells expressing adhesive (CD11b and CD62L) and functional (CD64 and HLA-DR) receptors. Moreover, the patient’s neutrophils expressed CD11b, CD16 and HLA-DR on their cell surface more intensively, than neutrophilic leukocytes from control group. These phenotypic changes in KC patients’ blood neutrophils occurred in parallel with pronounced decrease in immature cells numbers. The metabolic changes of neutrophil cytoplasmic compartment in KC patients were determined by a decrease in Glu6PDH activity (a key and initializing enzyme of the pentose phosphate cycle) and NADH-LDH (anaerobic glycolysis). Mitochondrial metabolism in neutrophils of KC patients was characterized by multidirectional changes in the activity of NAD- and NADP-dependent glutamate dehydrogenases (decreased activity of NAD-dependent and increased activity of NADP-dependent) and a decrease in NADH-MDH activity. The established features in mitochondrial enzymes activities suggest some disturbances of NAD-dependent processes that could lead to down-regulation of aerobic energy processes. We guess that the decreased activity of plastic and energy processes in blood neutrophils of KC patients could affect the receptor expression levels. By means of correlation analysis, we have found that the relationships in KC patients were determined by negative effects of NADHGDH and NADH-LDH activities upon expression of activation and adhesion receptors in blood neutrophils. Of these enzymes, only glutathione reductase activity in neutrophils from KC patients was positively linked with the CD23 and HLA-DR expression. Thus, an increase in activity of energy processes (e.g., coupling the tricarboxylic acid cycle to amino acid metabolism) in blood neutrophils from the patients with kidney cancer could stimulate expression levels of activation and adhesion receptors and potentially increase antitumor activity of neutrophils.

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