Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases

Abstract

Human monocytes are divided in three major populations; classical (CD14⁺CD16^-), non-classical (CD14^dimCD16⁺), and intermediate (CD14⁺CD16⁺). Each of these subsets is distinguished from each other by the expression of distinct surface markers and by their functions in homeostasis and disease. In this review, we discuss the most up-to-date phenotypic classification of human monocytes that has been greatly aided by the application of novel single-cell transcriptomic and mass cytometry technologies. Furthermore, we shed light on the role of these plastic immune cells in already recognized and emerging human chronic diseases, such as obesity, atherosclerosis, chronic obstructive pulmonary disease, lung fibrosis, lung cancer, and Alzheimer's disease. Our aim is to provide an insight into the contribution of human monocytes to the progression of these diseases and highlight their candidacy as potential therapeutic cell targets.

Keywords: atherosclerosis; diet; human monocytes; neurodegeneration; respiratory diseases.

Figure 1

Human monocyte subsets in health. Human monocytes mature in the bone marrow and are subsequently released into the circulation as CD14⁺ classical monocytes. Progressively, classical monocytes (CD14⁺CD16⁻) give rise to non-classical monocytes (CD14^dimCD16⁺) through an intermediate step of CD14⁺CD16⁺ monocytes. Classical monocytes in humans can be distinguished from the other two subsets by additional markers, such as CD36, CCR2, and CD64 and take part in the host's anti-microbial responses, such as adhesion to the endothelium, migration, and phagocytosis. Intermediate monocytes are characterized by their high expression of CCR5 and HLA-DR molecules and are involved in antigen processing and presentation and transendothelial migration. Non-classical monocytes divide into a SLAN⁺ and a SLAN⁻ population, express high levels of CX₃CR1 and specialize in complement and FcR-mediated phagocytosis, transendothelial migration and anti-viral responses. CM, classical monocytes; IM, intermediate monocytes; NCM, non-classical monocytes.

Figure 2

Monocyte functions in disease. Monocytes are involved in human diseases both by their direct functional effects, but also indirectly through their differentiation into macrophages. Diet influences the numbers of non-classical monocytes, monocyte migration, and cytokine production, effects which are counteracted by fasting. In addition, the epigenetic landscape is altered by metabolites in a process called innate immune memory. In atherosclerosis, monocytes differentiate into foam cells which secrete pro-inflammatory cytokines and chemokines, store lipids and are possibly involved in calcification. Differentiation of monocytes to DCs also contributes to antigen presentation. In the lung, changes in monocyte numbers are the most common observation in disease. Monocytes display high heterogeneity and their functions may be impaired like in COPD, whereas monocyte location seems to be crucial in lung cancer, with monocytes close to tumors being immunocompromised. Finally, monocytes infiltrate the brain in neurodegenerative diseases, such as Alzheimer's disease. CD36 and TREM2 are upregulated and enhance phagocytosis of Aβ plaques in monocyte-derived macrophages. NCM, non-classical monocyte; IM, interstitial macrophage.