Given that environmental factors such as pathogens, commensals and inflammation are likely to trigger the recruitment of monocytes and to promote their differentiation into macrophages and moDCs, it is possible that the proportion of BM-monocyte-derived cells in human tissues is higher than that in the tissues of laboratory mice. Besides macrophages and DCs, osteoclasts are cells that are also primarily derived from monocytes and their progenitors 97 , On the other hand, an infant who lacks IRF8 function shows normal osteoclast activity Given that IRF8 is essential for the development of monocytes in humans and mice but not cMoPs, at least in mice 20 , 88 , 91 , there might be different sources of osteoclast precursors in neonates and adults, e.
Monocytes have a wide range of plasticity that enables them to differentiate dynamically into diverse macrophages including tumor-associated macrophages, DCs and osteoclasts Fig. However, questions remain about how the plasticity of monocytes is imprinted during their development and how it is sustained after monocyte commitment.
In addition, after heart injury, neonatal monocytes fully repair the heart, whereas adult monocytes induce inflammation and scar formation , implying that epigenetic changes affect monocyte flexibility during life-stage progression. The mechanisms behind these epigenetic changes remain to be explored. In the context of ontogeny and phylogeny, monocytes emerge much later than macrophages 3—5 , implying that monocytes and macrophages have distinct roles in the body.
Compared to underwater life, organisms that live on land face many more pathogens and have a higher risk of tissue injury. Thus, in land animals, monocytes and other hematopoietic cells might have emerged out of immunological necessity. In addition, while the majority of tissue-resident macrophages are seeded at an embryonic stage from the YS 44 , 73—77 , the supply of YS-derived macrophages cannot be expected after birth, particularly when YS-derived macrophages are lost during tissue injury and regeneration.
Thus, monocytes replenish the lost macrophages, adapt to various microenvironments and maintain tissue homeostasis. The flexible differentiation capacity of monocytes is probably required for their physiological and urgent replenishment and adaptation. We thank N. Onai for valuable suggestions on the human cMoP study and M. Kanayama for helpful comments on this manuscript. Conflicts of interest statement: The authors declare no competing financial interests.
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Ly6C - monocytes secrete anti-inflammatory cytokine, IL upon in vivo bacterial infection. In vascular inflammation, Ly6C - monocytes are recruited to tissue and more likely to differentiate into M2 macrophages, which secrete anti-inflammatory cytokine and contribute to tissue repair Figure 1 [ 20 ]. Because CD14 is abundantly expressed on the surface of human monocytes and macrophages, it is used to mark human monocytes.
CCR5, known as a co-receptor for human immunodeficiency virus entry into macrophages, is also associated with CVD [ 31 , 33 ]. Their major function is phagocytosis. Gene expression profiling analysis indicates that human classical monocytes preferentially express genes involved in angiogenesis, wound healing, and coagulation [ 36 ]. In the steady state, classical MCs can differentiate into intermediate MCs, then differentiate into patrolling non-classical MCs in circulation.
Monocytes are differentiated from the committed precursor termed macrophage-DC precursor MDP mainly resident in bone marrow and differentiate into either dendritic cells or macrophages. On the other hands, Ly6C - monocytes, recruited at later phase of inflammation, attenuate inflammatory properties and differentiate toward M2 macrophages and contribute to angiogenesis, genesis of my fibroblasts, and collagen deposition Figure 1.
It is possible that monocytes and macropahge are highly plastic and can be crossly differentiated into different subsets in response to environment changes.
Inflammatory monocytes are the major cellular component in atherosclerotic plaque [ 47 ]. Accumulation of activated immune cells, including inflammatory monocytes and macrophages, and T lymphocytes in the vessel wall produce inflammatory cytokines and facilitate vascular inflammation.
Inflammatory monocytes may contribute to vascular inflammation not only by producing inflammatory cytokines, but also via CDmediated T cell activation. CD40 is a TNF receptor superfamily 5 member and is expressed in monocytes, macrophages, dendritic cells. CDCD40L expression on platelets enhances platelet activation and thrombosis [ 51 ]. CD40 and CD40L are both expressed on endothelial cells and vascular smooth muscle cells.
CD40 signaling induced the expression of adhesion molecules, matrix metalloproteinases and proinflammatory cytokines in macrophages and foam cell formation [ 54 ]. It was reported that monoclonal antibodies against CD40L reduced atherosclerosis rendered thromboembolic complications [ 55 ].
Similarly, monocytes are the major infiltrating immune cells in the ischemic brain in stroke. Monocyte infiltration is one of the earliest cellular response in stroke.
It occurs 4 hours after stroke and reaches maximum infiltration in 7 days [ 56 ]. Inflammation accompanying stroke plays an important role in secondary ischemic injury [ 57 ]. Infiltrated inflammatory cells can produce ROS, inflammatory cytokines and matrix metalloproteinase, inducing neuron injury directly or indirectly by inducing blood brain barrier BBB disruption, which can lead to edema, cerebral hemorrhage and a vicious circle of continuous influx of myeloid cells.
However, the inflammatory effects on the stroke process can be detrimental or protective, depending on the immune cell types, numbers and duration. A recently published paper indirectly supported the detrimental role of monocytes in stroke [ 58 ]. But the roles of different monocyte subsets in the pathogenesis of stroke remain unclear. The reason why the same CCR2 deficiency mice display different results is unknown, it may be due to different mouse breeding methods since pure knockout mouse cross-breeding for several generations may lead to gene changes, which may compensate for the designated gene defect.
To determine the roles of different monocyte subsets in stroke pathogenesis, more experiments should be conducted in the context of normal or combined disease settings like hyperlipidemia and hyperhomocysteinemia. To date, many studies have demonstrated the key roles of inflammatory and anti-inflammatory monocytes in response to inflammation or steady state in mouse models.
Inflammatory monocyte subset is a valuable biomarker for human inflammatory diseases, including cardiovascular diseases. Understanding the mechanism of monocyte differentiation will likely provide a potential therapeutic target for inflammatory monocytosis. Yasaka T, Mantich NM, Boxer LA, Baehner RL: Functions of human monocyte and lymphocyte subsets obtained by countercurrent centrifugal elutriation: differing functional capacities of human monocyte subsets.
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Curr Opin Lipidol , — Qu C, et al. Immunity , 71— Inflamm Bowel Dis , — This article is available under a Creative Commons License Attribution 4. This article has been cited by other articles in PMC. Abstract In humans, the monocyte pool comprises three subsets classical, intermediate, and nonclassical that circulate in dynamic equilibrium. Introduction The mononuclear phagocyte system comprises three types of cells: monocytes, macrophages, and DCs, as well as their committed bone marrow progenitors van Furth et al.
Results and discussion Characterization of human monocyte subset kinetics under steady state The literature has not always clearly distinguished between monocyte subsets, making interpretation confusing.
Open in a separate window. Figure 1. Table 1. Derived variables for in vivo human monocyte kinetics. Human endotoxemia provokes the early release of bone marrow monocytes We next investigated the response of monocytes to major systemic inflammation using the human experimental endotoxemia model Fig.
Figure 2. Classical human monocytes have the potential to give rise to intermediate and nonclassical monocytes Given the sequential maturation of monocyte subsets during healthy homeostasis and, reappearance of monocytes following endotoxin challenge, we investigated the developmental relationship between human monocytes subsets in a humanized animal model.
Figure 3. Materials and methods Subjects and ethics Subjects were healthy volunteers 20 males and 5 females. Deuterium labeling Deuterium labeling followed a shortened version of published protocols Macallan et al. Modeling of data A schematic of the model is shown in Fig.
Online supplemental material Fig. Acknowledgments We would like to thank the all the volunteers who participated in this study, Jamie Evans UCL for his assistance with the cell sorting, and Jonathan Alderman Yale University for coordinating phlebotomy and logistics. The authors declare no competing financial interests. References Arnold L. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.
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