Inflammation Resolution and the Induction of Granulocyte Apoptosis by Cyclin-Dependent Kinase Inhibitor Drugs

Abstract

Inflammation is a necessary dynamic tissue response to injury or infection and it's resolution is essential to return tissue homeostasis and function. Defective or dysregulated inflammation resolution contributes significantly to the pathogenesis of many, often common and challenging to treat human conditions. The transition of inflammation to resolution is an active process, involving the clearance of inflammatory cells (granulocytes), a change of mediators and their receptors, and prevention of further inflammatory cell infiltration. This review focuses on the use of cyclin dependent kinase inhibitor drugs to pharmacologically target this inflammatory resolution switch, specifically through inducing granulocyte apoptosis and phagocytic clearance of apoptotic cells (efferocytosis). The key processes and pathways required for granulocyte apoptosis, recruitment of phagocytes and mechanisms of engulfment are discussed along with the cumulating evidence for cyclin dependent kinase inhibitor drugs as pro-resolution therapeutics.

Keywords: AT7519; Mcl-1; R-roscovitine; efferocytosis; eosinophil; neutrophil.

Figure 1

Schematic diagram of intrinsic and extrinsic pathways of neutrophil apoptosis. The intrinsic pathway is instigated when apoptotic proteins outweigh antiapoptotic proteins of the Bcl-2 family and trigger mitochondrial outer membrane permeability (MOMP). The resulting release of cytochrome C, ATP and apoptotic protease activating factor-1 (APAF-1) activates caspase 9 and subsequently caspase 3. Mitochondria also release a second mitochondrial-derived activator of caspases (SMAC), which inhibits the inhibitor of apoptosis (IAP) and thereby enhances apoptosis. Cyclin dependent kinase inhibitors (CDKI) down regulate Mcl-1 of the Bcl-2 proteins, thereby initiating the first step of this pathway. The extrinsic pathway commences with ligation of a death receptor by TNF, Fas ligand or TRAIL. This results in the generation of the death-inducing signaling complex (DISC) cascade and this causes pro-caspase 8 cleavage. Caspase 8 can activate MOMP via cleavage and activation of Bid and can activate caspase 10, and subsequently executioner caspases, typically caspase 3.

Figure 2

Schematic diagram of some of the molecules involved in phagocyte recruitment and recognition and engulfment of apoptotic cells. Fine me signals including CX3CL1, Sphingosine 1-phosphate (S1P), nucleotides ATP and UTP and lysophosphatidylcholine attract phagocytes, along with inflammatory cytokines. Both direct and indirect binding of phosphatidylserine on apoptotic cells by various molecules is involved in phagocyte detection of these cells and for tethering and engulfment.