Acta NaturaeActa NaturaeActa Naturae2075-8251Acta Naturae Ltd2781510.32607/actanaturae.27815Research ArticlesЭкспериментальные статьиResearch ArticleThe transcriptional kinases CDK8/19 in the regulation of the macrophage inflammatory responseТранскрипционные киназы CDK8/19 в регуляции воспалительного ответа макрофаговNeznamovA. N.НезнамовА. Н.
Russian Federation
kubekina@genebiology.ruOparinaYu. A.ОпаринаЮ. А.
Russian Federation
kubekina@genebiology.ruDolmatovaD. M.ДолматоваД. М.
Russian Federation
kubekina@genebiology.ruIlchukL. A.ИльчукЛ. А.
Russian Federation
kubekina@genebiology.ruKubekinaM. V.КубекинаМ. В.
Russian Federation
kubekina@genebiology.ruRussian Academy of Science, Institute of Gene BiologyИнститут биологии гена РАНRussian Academy of Science, Engelhardt Institute of Molecular BiologyИнститут молекулярной биологии имени В.А. Энгельгардта РАН23072026182971070909202520032026Copyright ©; 2026, Neznamov A.N., Oparina Y.A., Dolmatova D.M., Ilchuk L.A., Kubekina M.V.Copyright ©; 2026, Незнамов А.Н., Опарина Ю.А., Долматова Д.М., Ильчук Л.А., Кубекина М.В.2026Neznamov A.N., Oparina Y.A., Dolmatova D.M., Ilchuk L.A., Kubekina M.V.Незнамов А.Н., Опарина Ю.А., Долматова Д.М., Ильчук Л.А., Кубекина М.В.https://creativecommons.org/licenses/by/4.0https://actanaturae.ru/2075-8251/article/view/27815

Macrophage dysfunction is a key pathogenetic mechanism in the progression of a wide range of human chronic inflammation conditions, including atherosclerosis, rheumatoid arthritis, and metabolic disorders. The CDK8 and CDK19 paralogous kinases, the subunits of the Mediator complex acting as transcription regulators, are essential modulators of the inflammatory response. This study addresses the role of CDK8/19 kinases in the macrophage inflammatory response via multiple mechanisms: activation of pro- and anti-inflammatory genes and surface markers, STAT1 pathway modulation, activation of glycolytic cascade genes, regulation of the dynamics of lipid inclusions, and phagocytic activity. Experiments have shown that CDK8 and CDK19 may exhibit functional divergence. Cdk19 knockout reveals that CDK19 plays a role in the suppression of the M1 response, as well as the regulation of lipid homeostasis and phagocytosis. Double Cdk8/19 knockout macrophages are characterized by an exacerbated anti-inflammatory response while preserving normal lipid accumulation and phagocytosis levels. Inhibition of CDK8/19 kinase activity reproduces these effects only partially, suggesting that both kinase-dependent and kinase-independent mechanisms of action exist. The identified effects reveal previously unknown regulation mechanisms of macrophage immunometabolism. Modulation of CDK8 and CDK19 activity can become a novel therapeutic target for a wide range of chronic inflammatory conditions and metabolic disorders associated with macrophage dysfunction.

Дисфункция макрофагов считается ключевым звеном патогенеза широкого спектра хронических воспалительных заболеваний человека, включая атеросклероз, ревматоидный артрит и метаболические нарушения. Важными модуляторами воспалительного ответа являются киназы CDK8 и CDK19, которые, будучи паралогами, входят в состав медиаторного комплекса и участвуют в регуляции транскрипции. В представленной работе изучали роль CDK8/19 в формировании воспалительного ответа макрофагов посредством множественных механизмов, таких как активация про- и противовоспалительных маркеров, модуляция пути STAT1, активация генов гликолитического каскада, динамика содержания липидных включений, фагоцитарная активность. Показано, что CDK8 и CDK19 могут обладать функциональной дивергенцией. Нокаут Cdk19 выявляет роль CDK19 как супрессора M1-воспаления, а также регулятора липидного гомеостаза и фагоцитоза. Макрофаги с двойным нокаутом Cdk8/19 характеризуются усилением противовоспалительного ответа при сохранении нормального уровня накопления липидов и фагоцитоза. Ингибирование киназной активности CDK8/19 воспроизводит лишь часть наблюдаемых эффектов, что указывает на наличие как киназозависимых, так и киназонезависимых механизмов их действия. Выявленные эффекты раскрывают ранее неизвестные механизмы регуляции иммунометаболизма макрофагов. Модуляция активности CDK8/19 может представлять собой новую стратегию терапии широкого круга хронических воспалительных заболеваний, в патогенезе которых ключевую роль играет дисфункция макрофагов.

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