Induction of Eosinophil Apoptosis by the Cyclin-Dependent Kinase Inhibitor AT7519 Promotes the Resolution of Eosinophil-Dominant Allergic Inflammation

Abstract

BackgroundEosinophils not only defend the body against parasitic infection but are also involved in pathological inflammatory allergic diseases such as asthma, allergic rhinitis and contact dermatitis. Clearance of apoptotic eosinophils by macrophages is a key process responsible for driving the resolution of eosinophilic inflammation and can be defective in allergic diseases. However, enhanced resolution of eosinophilic inflammation by deliberate induction of eosinophil apoptosis using pharmacological agents has not been previously demonstrated. Here we investigated the effect of a novel cyclin-dependent kinase inhibitor drug, AT7519, on human and mouse eosinophil apoptosis and examined whether it could enhance the resolution of a murine model of eosinophil-dominant inflammation in vivo.Methodology/Principal FindingsEosinophils from blood of healthy donors were treated with AT7519 and apoptosis assessed morphologically and by flow-cytometric detection of annexin-V/propidium iodide staining. AT7519 induced eosinophil apoptosis in a concentration dependent manner. Therapeutic administration of AT7519 in eosinophil-dominant allergic inflammation was investigated using an established ovalbumin-sensitised mouse model of allergic pleurisy. Following ovalbumin challenge AT7519 was administered systemically at the peak of pleural inflammation and inflammatory cell infiltrate, apoptosis and evidence of macrophage phagocytosis of apoptotic eosinophils assessed at appropriate time points. Administration of AT7519 dramatically enhanced the resolution of allergic pleurisy via direct induction of eosinophil apoptosis without detriment to macrophage clearance of these cells. This enhanced resolution of inflammation was shown to be caspase-dependent as the effects of AT7519 were reduced by treatment with a broad spectrum caspase inhibitor (z-vad-fmk).ConclusionsOur data show that AT7519 induces human eosinophil apoptosis and enhances the resolution of a murine model of allergic pleurisy by inducing caspase-dependent eosinophil apoptosis and enhancing macrophage ingestion of apoptotic eosinophils. These findings demonstrate the utility of cyclin-dependent kinase inhibitors such as AT7519 as potential therapeutic agents for the treatment of eosinophil dominant allergic disorders.

Wogonin Induces Eosinophil Apoptosis and Attenuates Allergic Airway Inflammation

“…Although one study group found that the CDKi roscovitine induced eosinophil apoptosis in vitro, they did not find any significant effect of roscovitine when administered in a model of allergic inflammation in vivo with respect to airway or tissue eosinophilia, nor was any difference in goblet cell mucus production noted (39). This is in partial contrast to a previous study by our group in which we used a different CDKi (AT7519) where administration in a model of allergic pleurisy was able to reduce eosinophil numbers at the site of inflammation secondary to enhanced eosinophil apoptosis (40), although the functional effects of this CDKi-mediated reduction in eosinophils were not investigated. Similarly, in a recent investigation, mice deficient in Siglec-F signaling demonstrated enhanced eosinophilic airway inflammation, presumed secondary to a reduction in eosinophil apoptosis (41).…”

Gedunin, a natural tetranortriterpenoid, modulates T lymphocyte responses and ameliorates allergic inflammation

“…Glucocorticoids, such as dexamethasone, have been extensively used to treat allergic diseases such as asthma. Glucocorticoid induction of eosinophil apoptosis has been proposed as a key mechanism to reduce tissue and circulating eosinophil numbers [59][60][61][62][63]. Our results clearly demonstrate that gedunininduced eosinophil arrest is a result of the impairment of the T cell-dependent eosinophilotactic mediators IL-5, CCL11 and CCL5, even though gedunin also presents direct effects on isolated eosinophils (impairing chemotaxis), as we have previously demonstrated [30].…”

Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo

“…CDK inhibitor drugs drive neutrophil and eosinophil apoptosis in vitro and enhance resolution of inflammation in vivo 12133637. Previous work from our group found that the flavone compound wogonin, which inhibits CDK9 in cancer cells38 can drive neutrophil apoptosis in a zebrafish tailfin wounding model21.…”