The Transcriptional Kinases CDK8/19 in the Regulation of the Macrophage Inflammatory Response.

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.