Mitochondria in monocytes and macrophages-implications for translational and basic research

Abstract

The mitochondrion plays a crucial role in the immune system particularly in regulating the responses of monocytes and macrophages to tissue injury, pathogens, and inflammation. In systemic diseases such as atherosclerosis and chronic kidney disease (CKD), it has been established that disruption of monocyte and macrophage function can lead to chronic inflammation. Polarization of macrophages into the pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes results in distinct metabolic reprograming which corresponds to the progression and resolution of inflammation. In this review, we will discuss the role of the mitochondrion in monocyte and macrophage function and how these cells specifically influence the pathophysiology of atherosclerosis and CKD. We propose that assessing monocyte bioenergetics in different disease states could (1) enhance our understanding of the energetic perturbations occurring in systemic inflammatory conditions and (2) aid in identifying therapeutic interventions to mitigate these disorders in patients.

Keywords: Atherosclerosis; Biomarker; Chronic kidney disease; Macrophage; Monocyte; Oxidative stress.

Figure 1. Differentiation and metabolism of monocytes and tissue macrophages

The circulating monocyte is shown exiting the vasculature and proceeding into the tissue and differentiating into a tissue macrophage (M0). These cells utilize oxidative phosphorylation to meet their energetic demand. Upon differentiation, the cytokine and pathogen environment directs their fate to either the M1 or M2 phenotype in the presence of TNFα, PAMPS, INFγ, or TGFβ and IL-10, respectively. M1 macrophages rely on glycolysis for energy production and as such have a lower ratio of oxidative phosphorylation to glycolysis. On the other hand, M2 macrophages preferentially utilize oxidative phosphorylation, and so have a higher ratio of oxidative phosphorylation to glycolysis.

Figure 2. Physiological and pathological fates of macrophages

A. Scheme depicting physiological monocyte extravasation into the subintimal space of a vessel and differentiation into a macrophage to clear oxidized LDL (oxLDL) through the CD36 scavenger receptor. These macrophages can then differentiate into M2 macrophages to resolve the inflammation as well as clear damaged cells by efferocytosis. B. In atherosclerosis, impaired recruitment and migration of monocytes facilitates increased macrophage differentiation in the subintimal space. High levels of ox-LDL leads to oxidative stress and bioenergetic dysfunction in macrophages which may proceed to apoptosis or the M1 macrophage phenotype.