Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases

Abstract

Monocytes express various receptors, which monitor and sense environmental changes. Monocytes are highly plastic and heterogeneous, and change their functional phenotype in response to environmental stimulation. Evidence from murine and human studies has suggested that monocytosis can be an indicator of various inflammatory diseases. Monocytes can differentiate into inflammatory or anti-inflammatory subsets. Upon tissue damage or infection, monocytes are rapidly recruited to the tissue, where they can differentiate into tissue macrophages or dendritic cells. Given the rapid progress in monocyte research from broad spectrum of inflammatory diseases, there is a need to summarize our knowledge in monocyte heterogeneity and its impact in human disease. In this review, we describe the current understanding of heterogeneity of human and murine monocytes, the function of distinct subsets of monocytes, and a potential mechanism for monocyte differentiation. We emphasize that inflammatory monocyte subsets are valuable biomarkers for inflammatory diseases, including cardiovascular diseases.

Figure 1

Human MC and Mϕ differentiation, and distinct subset functions. Human CD14⁺⁺CD16^- classical MCs leave the bone marrow in a CC-chemokine receptor 2 (CCR2)-dependent manner. In the steady state, classical MCs can differentiate into intermediate MCs, then differentiate into patrolling non-classical MCs in circulation. Classical MCs have a high antimicrobial capability due to their potent capacity of phagocytosis, and secrete ROS and IL-10 upon LPS stimulus, whereas intermediate and non-classical MCs secrete inflammatory cytokines, TNFα and IL-1β upon inflammatory stimulation. During inflammation, classical and intermediate MCs are tethered and invade tissue by interaction of complementary pair CCR2/CCL2(MCP1) or/and CCR5/CCL5(RANTES) in a VLA1/VCAM1 dependent manner. MCs then mature to M1Mϕ in tissue and present self-antigen via MHC-I/II to TCR leading to TC activation. Non-classical MCs patrol the vessel wall and invade by interaction of complementary pair of CX3CR1/CCL3 via LAF/ICAM1-dependent manner. TC, T cell; MC, monocyte; Mϕ, macrophage; EC, endothelial cells; inf., inflammatory; α-inf. Anti-inflammatory; TCR, T cell receptor; HLA-DR, human leukocyte antigen DR (a major histocompatibility complex class II (MHC-II)).

Figure 2

Murine MC and Mϕ differentiation, and distinct subset functions. Mouse Ly6C + MCs leave the bone marrow in a CC-chemokine receptor 2 (CCR2)-dependent manner. In the steady state, Ly6C + MCs differentiate into Ly6C- MCs in the circulation. Ly6C- MCs are recruited into normal tissue by interaction of complementary pair CX3CR1/CCL3 via a LAF/ICAM1-dependent manner and become tissue resident Mϕ/DCs. Ly6C + MCs have a high antimicrobial capability due to their potent capacity for phagocytosis, and secrete ROS, TNFα, and IL-1β, whereas Ly6C- MCs secrete anti-inflammatory cytokine IL-10 upon in vivo bacteria infection. In vascular inflammation, Ly6C + MCs are tethered and invade tissue by interaction complimentary pair of CCR2/CCL2(MPC-1) via a VLA-1/VCAM1-dependent manner, then mature to inflammatory M1Mϕ. M1Mϕ are distinguished by secretion of pro-inflammatory cytokines, TNFα and IL-6 and contribute to tissue degradation and T cell activation. Ly6C- MCs are recruited to tissue and differentiate into M2Mϕ, which secrete anti-inflammatory cytokine and contribute to tissue repair. TC, T cell; MC, monocyte; Mϕ, macrophage; EC, endothelial cells; DC, dendritic cell; inf., inflammatory; α-inf. Anti-inflammatory; TCR, T cell receptor; HLA-DR, human leukocyte antigen DR (a major histocompatibility complex class II (MHC-II)).