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

Jennifer A Cartwright,Christopher D Lucas,Adriano G Rossi

doi:10.3389/fphar.2019.00055

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.

Highlights

This review focuses on the use of cyclin dependent kinase inhibitor drugs to pharmacologically target this inflammatory resolution switch, through inducing granulocyte apoptosis and phagocytic clearance of apoptotic cells
The mechanisms by which apoptosis is induced in granulocytes are consistently highlighted as that of the caspase dependent intrinsic pathway through myeloid cell leukemia factor-1 (Mcl-1) reduction and increased mitochondrial membrane potential
CDK9 has been demonstrated to be the critical target of cyclin-dependent kinase inhibitor (CDKI) in inducing neutrophil apoptosis

Summary

Introduction

This review focuses on the use of cyclin dependent kinase inhibitor drugs to pharmacologically target this inflammatory resolution switch, through inducing granulocyte apoptosis and phagocytic clearance of apoptotic cells (efferocytosis). Tyrosine receptor kinase Mer, has been shown to be a crucially expressed protein for alveolar macrophage phagocytosis of apoptotic eosinophils, and without this binding mechanism, increased inflammation, delayed resolution and increased airway responsiveness occur (Felton et al, 2018). When CDKIs were used on neurons, another terminally differentiated cell type, there was the opposite effect of prolonged cellular survival (Dhavan and Tsai, 2001) while CDKI treatment of cardiomyocytes inhibited doxorubicin-induced apoptosis via reduced CDK2-dependent expression of Bim (Xia et al, 2018).

Results

Conclusion