CDK7, CDK9, or CDK11 Inhibition Reduces Neutrophil-Driven Inflammation and Tissue Damage in Experimental Autoimmune Models

Cyclin-dependent kinases are involved in basic cellular processes like regulation of cell-cycle progression and transcription. However, recent data also indicate a specific role in terminally differentiated neutrophils by promoting reactive oxygen species (ROS) release, degranulation, neutrophil extracellular trap (NET) formation, or apoptosis. Thus, we investigated the effect of pharmacological CDK inhibition on IC-activated neutrophil functions. Inhibitors targeting CDK1, 2, 4/6, 7, 9, 11, and 12 showed effects on different neutrophil functions (surface activation marker expression, ROS release, adhesion, apoptosis) in vitro . To analyse the inhibitors in a more translational approach, we proceeded with the systemic application of the effective inhibitors in a murine antibody transfer-induced local EBA model. In this predominantly neutrophil-driven model, we observed a reduction of disease severity upon treatment with CDK7, 9, or 11 inhibitors. Inhibiting these CDKs with topical THZ2, MC180295, or OTS964 also improved the clinical phenotype. Therefore, the most efficient inhibitor, MC180295, was validated in two other IC-mediated models of autoimmune disease: Serum-transfer arthritis, which also, but not exclusively depends on neutrophils and ITP, which is considered neutrophil-independent. Here, an effect in STA was observed, but not in ITP. Hence, we show the therapeutic potential of CDK7, 11, and especially 9 inhibition in IC-driven neutrophil-mediated diseases such as RA and EBA.