Role of Mitochondria in the Regulation of Effector Functions of Granulocytes

Abstract

Granulocytes (neutrophils, eosinophils, and basophils) are the most abundant circulating cells in the innate immune system. Circulating granulocytes, primarily neutrophils, can cross the endothelial barrier and activate various effector mechanisms to combat invasive pathogens. Eosinophils and basophils also play an important role in allergic reactions and antiparasitic defense. Granulocytes also regulate the immune response, wound healing, and tissue repair by releasing of various cytokines and lipid mediators. The effector mechanisms of granulocytes include the production of reactive oxygen species (ROS), degranulation, phagocytosis, and the formation of DNA-containing extracellular traps. Although all granulocytes are primarily glycolytic and have only a small number of mitochondria, a growing body of evidence suggests that mitochondria are involved in all effector functions as well as in the production of cytokines and lipid mediators and in apoptosis. It has been shown that the production of mitochondrial ROS controls signaling pathways that mediate the activation of granulocytes by various stimuli. In this review, we will briefly discuss the data on the role of mitochondria in the regulation of effector and other functions of granulocytes.

Keywords: apoptosis; degranulation; extracellular traps; granulocytes; inflammation; leukotrienes; mitochondria; mitochondria-targeted antioxidants; mitochondrial ROS production; oxidative burst.

Figure 1

Scheme illustrating the mitochondrial control of granulocyte effector functions, leukotriene synthesis, and apoptosis. ROS, reactive oxygen species; NOX2, NADPH oxidase 2; NETs, EETs, BETs, extracellular DNA-containing traps released from neutrophils, eosinophils, and basophils, respectively; LTs, leukotrienes; LTB4, leukotriene B4. Interactions that have not been verified experimentally are marked with a “?”.

Figure 2

Regulation of effector functions of neutrophils by mitochondrial ROS. Degranulation, oxidative burst, and NETosis can be stimulated by pathogens through specific receptors (such as the specific G protein-coupled fMLP receptor) or by direct Ca²⁺ mobilization (as modeled with the calcium ionophore A23187). The subsequent accumulation of Ca²⁺ in the mitochondrial matrix leads to the opening of nonselective mitochondrial pores (mPTP) and the formation of mitochondrial ROS (mtROS). mtROS released into the cytosol can activate NADPH oxidase (NOX2), degranulation, and NETosis through protein kinase C (PKC) activation, as well as through several unidentified signaling pathways. ROS produced by NOX2 also stimulate degranulation and NETosis. Receptor-dependent activation includes stimulation of phospholipase C (PLC), which catalyzes the synthesis of inositol triphosphate (IP3) and diacylglycerol (DAG). DAG is a powerful stimulus for PKC, so this branch of neutrophil activation is independent of mitochondria. This is modeled by the synthetic analogue of DAG, phorbol 12-myristate 13-acetate (PMA), which stimulates the effector functions of neutrophils independently of mitochondria.