mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-RBS-2508mimmun-2508Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESВзаимосвязи между сывороточной концентрацией HMGB1 и субпопуляционным составом циркулирующих моноцитов у пациентов с субклиническим атеросклерозомRelationships between serum HMGB1 concentration and subpopulation composition of circulating monocytes in patients with subclinical atherosclerosishttps://orcid.org/0000-0001-5902-3803ГенкельВ. В.GenkelV. V.

Генкель Вадим Викторович — кандидат медицинских наук, доцент кафедры пропедевтики внутренних болезней.

454048, Челябинск, ул. Шаумяна, 118, кв. 22.

Тел.: 8 (951) 441-70-61.

Vadim V. Genkel - PhD (Medicine), Associate Professor, Department of Propaedeutics of Internal Medicine, South-Ural State Medical University.

454048, Chelyabinsk, Shaumyan str., 118, apt 22.

Phone: 7 (951) 441-70-61.

henkel-07@mail.ruhttps://orcid.org/0000-0002-0901-8042ДолгушинИ. И.DolgushinI. I.

Долгушин Илья Ильич— доктор медицинских наук, профессор, заслуженный деятель науки РФ, академик РАН, президент ЮУГМУ, заведующий кафедрой микробиологии, вирусологии, иммунологии, директор НИИ иммунологии ЮУГМУ.

Челябинск.

Ilya I. Dolgushin - PhD, MD (Medicine), Professor, Corresponding Member, Russian Academy of Sciences, Honored Worker of Science of the Russian Federation, President of South-Ural State Medical University, Head of the Department of Microbiology, Virology, Immunology, South-Ural State Medical University.

Chelyabinsk.

dol-ii@mail.ruhttps://orcid.org/0000-0002-5960-4189БатуринаИ. Л.BaturinaI. L.

Батурина Ирина Леонидовна — кандидат медицинских наук, старший научный сотрудник НИИ иммунологии.

Челябинск.

Irina L. Baturina - PhD (Medicine), Senior Research Associate, Research Institute of Immunology, South-Ural State Medical University.

Chelyabinsk.

irisha_baturina@mail.ruhttps://orcid.org/0000-0002-0536-0924СавочкинаА. Ю.SavochkinaA. Yu.

Савочкина Альбина Юрьевна — доктор медицинских наук, профессор кафедры клинической лабораторной Диагностики, главный научный сотрудник НИИ иммунологии.

Челябинск.

Albina Yu. Savochkina - PhD, MD (Medicine), Professor, Department of Clinical Laboratory Diagnostics, Chief Research Associate, Research Institute of Immunology, South-Ural State Medical University.

Chelyabinsk.

alina7423@mail.ruhttps://orcid.org/0000-0002-3900-9278НикушкинаК. В.NikushkinaK. V.

Никушкина Карина Викторовна — кандидат медицинских наук, ведущий научный сотрудник НИИ иммунологии.

Челябинск.

Karina V. Nikushkina - PhD (Medicine), Leading Research Associate, Research Institute of Immunology, South-Ural State Medical University.

Chelyabinsk.

knikushkina81@gmail.comhttps://orcid.org/0000-0002-9084-0577МинасоваА. А.MinasovaA. A.

Минасова Анна Александровна — кандидат биологических наук, доцент кафедры микробиологии, вирусологии, иммунологии.

Челябинск.

Anna A. Minasova - PhD (Biology), Associate Professor, Department of Microbiology, Virology, Immunology, South-Ural State Medical University.

Chelyabinsk.

pandora_anna@mail.ruhttps://orcid.org/0000-0003-0658-7626ПыховаЛ. Р.PykhovaL. R.

Пыхова Любовь Романовна — старший преподаватель кафедры микробиологии, вирусологии, иммунологии.

Челябинск.

Lyubov R. Pykhova - Senior Lecturer, Department of Microbiology, Virology, Immunology, South-Ural State Medical University.

Chelyabinsk.

lyubov_pykhova@mail.ruhttps://orcid.org/0000-0002-0357-5702КузнецоваА. С.KuznetcovaA. S.

Кузнецова Алла Сергеевна — кандидат медицинских наук, доцент кафедры госпитальной терапии.

Челябинск.

Alla S. Kuznetsova - PhD (Medicine), Associate Professor, Department of Clinical Therapy, South-Ural State Medical University.

Chelyabinsk.

kuzja321@mail.ruhttps://orcid.org/0000-0002-7731-7730ШапошникИ. И.ShaposhnikI. I.

Шапошник Игорь Иосифович — доктор медицинских наук, профессор, заведующий кафедрой пропедевтики внутренних болезней.

Челябинск.

Igor I. Shaposhnik - PhD, MD (Medicine), Professor, Head, Department of Propaedeutics of Internal Medicine, South-Ural State Medical University.

Chelyabinsk.

shaposhnik@yandex.ruЮжно-Уральский государственный медицинский университет Министерства здравоохранения РФРоссияSouth-Ural State Medical UniversityRussian Federation202213072022244807820Copyright © Генкель В.В., Долгушин И.И., Батурина И.Л., Савочкина А.Ю., Никушкина К.В., Минасова А.А., Пыхова Л.Р., Кузнецова А.С., Шапошник И.И., 20222022Генкель В.В., Долгушин И.И., Батурина И.Л., Савочкина А.Ю., Никушкина К.В., Минасова А.А., Пыхова Л.Р., Кузнецова А.С., Шапошник И.И.Genkel V.V., Dolgushin I.I., Baturina I.L., Savochkina A.Y., Nikushkina K.V., Minasova A.A., Pykhova L.R., Kuznetcova A.S., Shaposhnik I.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2508

Хроническое стерильное низкоинтенсивное воспаление является важнейшим механизмом развития и прогрессирования атеросклероза. В условиях персистирующего неразрешающего-ся (non-resolving) воспаления, наблюдающегося в сосудистой стенке и атеросклеротической бляшке (АСБ), происходит постоянное повреждение тканей, приводящее к повышенному образованию эндогенных молекулярных паттернов, ассоциированных с опасностью (danger associated molecular patterns, DAMP). Один из прототипических DAMP является негистоновый хромосомный белок HMGB1. Попадая во внеклеточное пространство, HMGB1 действует как DAMP и индуцирует воспаление путем связывания с паттерн-распознающими рецепторами (TLR2, TLR4, RAGE, CD36 и т.д.). В целом ряде клинических исследований было установлено повышение уровня HMGB1 в крови у пациентов с ишемической болезнью сердца и атеросклеротическим заболеванием артерий нижних конечностей, а также его взаимосвязи с бременем атеросклероза коронарных артерий. В то же время механизмы прогрессирования атеросклероза, опосредованные HMGB1, на сегодняшний день изучены лишь частично.

Цель исследования — изучить взаимосвязь между уровнем сывороточного HMGB1 и субпопуляционным составом циркулирующих моноцитов у пациентов с субклиническим атеросклерозом в возрасте 40-64 лет.

В исследование включали пациентов в возрасте 40-64 лет с субклиническим атеросклерозом периферических артерий. Концентрацию HMGB1 в сыворотке крови определяли с использованием наборов для иммуноферментного анализа (Human HMGB1/HMG-1 ELISA Kit, NBP2-62766, Novus Biologicals, США). Порог определения содержания HMGB1 в сыворотке крови составлял 18,75 пг/мл, диапазон измерения — 31,25-2000 пг/мл. Фенотипирование субпопуляций циркулирующих моноцитов проводили методом проточной цитометрии на аппарате Navios 6/2 (Beckman Coulter, США).

Увеличение концентрации HMGB1 в сыворотке крови ассоциировалось с уменьшением количества классических М2-моноцитов и увеличением промежуточных и М1-моноцитов. Кроме того, увеличение концентрации HMGB1 было связано с увеличением количества классических, промежуточных и неклассических моноцитов, экспрессирующих CD36 и TLR2. По мере увеличения концентрации HMGB1 от Q1 до Q4 наблюдалось увеличение количества классических (p = 0,001) и промежуточных моноцитов (p = 0,006), но не неклассических (p = 0,147). По мере увеличения концентрации HMGB1 от Q1 до Q4 происходило увеличение количества классических (p < 0,0001), промежуточных (p < 0,0001) и неклассических (p < 0,0001) моноцитов, экспрессирующих CD36. Также было установлено увеличение количества промежуточных (p = 0,022; p1, 4 = 0,034) и неклассических (p = 0,002; p1, 4 = 0,035) моноцитов, экспрессирующих TLR2. По данным корреляционного анализа было установлено, что концентрация IL-1β прямо коррелировала с количеством М1-моноцитов (г = 0,268; p = 0,035) и обратно — с количеством М2-моноцитов (г = -0,376; p = 0,003).

Увеличение концентрации HMGB1 в сыворотке крови пациентов с субклиническим атеросклерозом ассоциировалось с уменьшением количества классических и М2-моноцитов, и увеличением — промежуточных и М1-моноцитов, а также с увеличением количества промежуточных и неклассических моноцитов, экспрессирующих CD36 и TLR2. Уровень IL-1β прямо коррелировал с концентрацией HMGB1 и количеством М1-моноцитов.

Chronic non-infectious inflammation of low intensity is the most important mechanism of development and progression in atherosclerosis. Under the conditions of persistent non-resolving inflammation observed in the vascular wall and atherosclerotic plaque (ASB), permanent tissue damage occurs, thus leading to increased formation of endogenous danger-associated molecular patterns (DAMPs). The non-histone chromosomal protein HMGB1 may be regarded as a prototypical DAMPs. HMGB1 acts as a DAMP if entering the extracellular space, causing inflammation by its binding to pattern-recognizing receptors (TLR2, TLR4, RAGE, CD36, etc.). A number of clinical studies have revealed higher HMGB1 levels in the blood of patients with coronary heart disease and atherosclerotic disease of the lower limb arteries, as well as its interrelations with the burden of coronary artery atherosclerosis. Currently, the mechanisms of HMGB1-mediated atherosclerosis progression are studied only fragmentary. The aim of our study was to investigate relationships between the serum HMGB1 level and subsets of circulating monocyte subpopulations in patients with subclinical atherosclerosis.

The study enrolled patients aged 40-64 years with subclinical atherosclerosis of peripheral arteries. Serum HMGB1 concentration was determined using enzyme immunoassay kits (Human HMGB1/HMG-1 ELISA Kit, NBP2-62766, Novus Biologicals, USA). The serum HMGB1 threshold was 18.75 pg/ml, whereas the measurement range was 31.25 to 2000 pg/ml. Phenotyping of the blood monocyte subpopulations was performed by flow cytometry using Navios 6/2 device (Beckman Coulter, USA).

An increase in serum HMGB1 concentration was associated with decreased number of classical M2 monocytes, and an increase in intermediate and M1 monocytes. Moreover, an increase in HMGB1 concentration was associated with higher numbers of classical, intermediate, and non-classical monocytes expressing CD36 and TLR2. Increased HMGB1 concentration (from Q1 to Q4) correlated with higher numbers of classical (p = 0.001) and intermediate monocytes (p = 0.006) but not with non-classical phenotypes (p = 0.147). Upon increase of HMGB1 concentration (Q1 to Q4), we have found an increase in the number of classical (p < 0.0001), intermediate (p < 0.0001), and non-classical (p < 0.0001), CD36-expressing monocytes. An increased number of intermediate (p = 0.022; p1, 4 = 0.034) and non-classical, TLR2-expressing monocytes was also revealed (p = 0.002; p1, 4 = 0.035). By mean of correlation analysis, IL-1β concentrations showed direct correlation with the number of M1 monocytes (r = 0.268; p = 0.035) and inverse relation with the number of M2 monocytes (r = -0.376; p = 0.003).

Increased serum HMGB1 concentration in patients with subclinical atherosclerosis was associated with decreased numbers of classical and M2 monocytes, as well as higher numbers of intermediate and M1 monocytes, like as with increased contents of intermediate and non-classical monocytes expressing CD36 and TLR2. IL-1β levels directly correlated with HMGB1 concentration and the number of Mi-monocytes.

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