Introduction:
The mononuclear phagocyte system (MPS) is a part of the immune system that consists of cell family derived from progenitor cells in the bone marrow. These cells differentiate to form blood monocytes and circulate in the blood and at last they enter tissues to become resident tissue macrophages[1]. In the last four decades there are several researches to detect the ontogeny of mononuclear phagocytes and it was found that there are several cellular similarities between the morphological, cytochemical and functional characteristics of monoblasts, pro-monocytes, monocytes and macrophages, so all these cells were recognized as members of a single cell family, collectively called mononuclear phagocytes and the concept of the mononuclear phagocyte system was developed.[2]
In the late 19th and early 20th centuries, eminent pathologist K.A.L. Aschoff along with several other pathologists, included macrophages (histiocytes) along with reticulum cells and phagocytic endothelia and proposed the concept of reticuloendothelial system, as all of these cells could internalize certain dyes. Later, however, it was found that endothelial cells are not phagocytes and the uptake of dyes is based on a completely different cellular mechanism. Hence they abandoned the term 'reticuloendothelial system'.[2],[3] In contrast van furth gave the concept of mononuclear phagocytic system and stated that all macrophages, either present in infection or residing in tissue at normal steady state derived from monocytes.[3]
Origin of mononuclear phagocyte system: Regarding formation of variety of blood cell from hematopoietic stem cell three models have been proposed. These are hierarchical model, stochastic model and sequential model.[2]
As per hierarchical model hematopoietic stem cell commits to a common myeloid precursor and a common lymphoid precursor. The common myeloid precursor generates precursors of megakaryocytes, erythrocytes, granulocytes and monocytes / macrophages, whereas precursor for T- and B-cells and NK cells derived from common lymphoid precursor.[2]
Stochastic model suggests that the commitment decision of haematopoietic precursors is stochastic which can occur at any time. [2]
Sequential model shows that precursors derived from hematopoietic stem cells express the potential for megakaryocyte, erythrocyte, granulocyte, monocyte, B-cell, T-cell and NK cell development progressively.[2]
In foetus Haematopoietic stem cells originate from the yolk sac which migrate to the foetal liver and develop immature mononuclear phagocytes.[2] On the other hand in adults bone marrow hematopoietic stem cells give rise to monoblast which differentiate into promonocyte, monocyte and macrophages which is short lived, nondividing terminating cells of mononuclear phagocyte system. Beside macrophages which are present during inflammation there are certain macrophages which are present under normal steady condition. These are microglia in brain, osteoclasts in bone and tissue macrophage such as kupffer cells in liver; histiocytes in connective tissue and skin; free macrophages in body cavities; free and fixed macrophages in spleen, lymph node, bone marrow and thymus; and macrophages in other various tissues.[3]
Current models states that blood monocytes, majority of macrophages and most dendritic cells originate in vivo from hematopoietic stem cell-derived progenitors which is having myeloid restricted differentiation potentiality.[4]

Genetic control of generation of the MPS:
Exact interaction between specific gene and transcription factors is very essential for specification of blood cell lineage. Colony stimulating factors (CSFs) are secreted glycoprotein. They bind to receptors which are located on surface of hematopoietic stem cells and activate intracellular signalling pathway to proliferate and differentiate blood cells, especially white blood cells. There are main three natural colony stimulating factors. These are colony stimulating factor- 1 (CSF-1) , colony stimulating factor-2(CSF-2) and colony stimulating factor-3(CSF-3).CSF-1 is also called macrophage colony stimulating factor(MCSF). They secret cytokine, which take major role in differentiation of macrophages from hematopoietic stem cells. In mononuclear phagocyte system colony stimulating factor-1(CSF-1) play the key role in proliferation and differentiation of all mononuclear phagocytic cells.CSF-1 binds to it receptor protein colony stimulating factor -1R (CSF-1R) on the cell surface and is encoded by c-fms proto oncogene for activation of cells.[2] The expression of CSF-1R gene is dependent on the expression of transcription factor PU-1.Hence expression of PU-1 as well as CSF-1R is very critical for myelopoiesis, macrophage differentiation as well as generation of mononuclear phagocyte system.[2]
PU.1 is called master transcription factor. It is not only essential for development of myeloid lineages but it also prevents the activation of genes which plays major role to differentiate other pathways.[2]

Cells of mononuclear phagocyte system :
Monocytes - Monocytes are produced from its hematopoietic precursors stem cell monoblasts. They are the largest corpuscles in the blood. About one to three days monocytes circulate in the bloodstream and then move into tissues throughout the body. In the tissues they mature into different types of macrophages at different anatomical locations. Monocytes in tissues differentiate into tissue resident macrophages or dendritic cells. Monocytes, their macrophage and dendritic-cells serve mainly three functions in the immune system. These are phagocytosis, antigen presentation, and cytokine production. Monocytes migrate from blood to tissue during infection are equipped with pathogen recognition receptors and chemokines receptors.

Monoblasts & promonocytes -Monoblast develop from pluripotent hematopoietic stem cells which in turn mature into pro monocytes, monocytes and at last into macrophages.

Macrophages: Monocytes differentiate into macrophages in tissue and helps in innate as well as adaptive immunity. They are resident phagocytes in lymphoid and non-lymphoid tissues and help in clearing of apoptotic cells and production of growth factor. A broad range of pathogen recognition receptors are attached with macrophages which make them efficient for phagocytosis and production of inflammatory cytokines.[5]
Dendritic cell: Dendritic cells are antigen presenting cells. They capture antigen, process them and present them on the cell surface. Along with regulation of adaptive immune response dendritic cells maintain B cell function and recall response. In human the dendritic cell originates from myeloid precursor consider as classical dendritic cell whereas plasmacytoid dendritic cells have lymphoid lineage.
Classical Dendritic cells (cDCs): The main functions of these cells are antigen processing and its presentation. They show high phagocytic activity when they are immature whereas mature cells shows high cytokine producing capacity. [6],[7] Classic dendritic cells are present in human circulation and move from tissues to the T-cell and B-cell zones of lymphoid organs via afferent lymphatics and high endothelial venules. They are generally short-lived, replaced by blood-borne precursors and T cell responses both in the steady-state and during infection. [8],[9]
Plasmacytoid Dendritic Cells (PDCs): These cells have lymphoid lineage and are relatively long lived compared to classical dendritic cells. These cells are present in bone marrow as well as all peripheral organs and produce massive type I interferons (IFN), as a result they respond well against viral infections. Plasmacytoid dendritic cells carry immunoglobulin as well as they act as antigen presenting cells and control T cell responses[10].

Function of mononuclear phagocyte system:
The main function of mononuclear phagocyte system is phagocytosis. It is mainly done by Macrophages.The antigens liberated by macrophages activate the B lymphocytes & helper T lymphocytes. Cells of this system Secrete IL-1, IL-6, and IL-12 in which IL-1 accelerates the maturation & proliferation of specific B lymphocytes & T lymphocytes, IL-6 causes growth of B lymphocytes & production of antibodies whereas IL-12 influences the T helper cells. These cells also Secret TNF -alpha and TNF -beta. TNF-alpha causes necrosis of tumor & activates immune system on the other hand TNF-beta stimulates immune system & causes vascular response in addition. The cells secrets platelet derived growth factor (PDGF) which accelerates repair of damaged blood vessel & wound healing. Macrophages remove carbon particle & silicone; destroy senile red cells and hemoglobin. Macrophage also acts as an antigen presenting cell to sensitized T cell.

Disease associated with monocyte macrophage cell line-
Numerous human disorders are associated with abnormalities of cells which are having macrophage like origin.[11]
These are

• Mild blood monocytosis which may be associated with infectious, inflammatory or collagen vascular diseases.
• Neoplastic proliferation of histiocytes which are seen in monocytic leukemia,malignant histiocytosis.
• Histiocytic proliferation of unknown origin such as sarcoidosis,granulomatous vasculitides and Wegener granulomatosis.
• reactive proliferation secondary to infection as an example Tuberculosis.
• chemical exposure such as beryllium and zirconium salts. [11]

In monocyte - macrophage dysfunction syndrome there are subtle defect in macrophage function which impair host defence. These defects and its consequent situations are

• Chemotaxis - present in Neoplasia
• Abnormal degranulation - Chediak Higashi syndrome
• Abnormal oxygen metabolism - Chronic granulomatous disease
• Suppressor monocytes - Miliary tuberculosis
• Suppressor monocytes - Lepromatous leprosy
• Chemotaxis,Suppressor monocytes - Disseminated fungal infection
• Chemotaxis,Microbial killing - Glucocorticoid treatment
• Neoplastic proliferation of macrophages - Hodgkin disease [11]

A number of recent studies showed that there are macrophage dysfunctions in neoplastic diseases.These dysfunctions can be considered in relation to cell maturation, migration and chemotaxis, phagocytosis, cytotoxicity and related phenomenon, lysozyme secretion and macrophages in malignant tumors.[12]
Scanning electron microscopic studies showed that the surface appearance of macrophages were more varied in lymphoma.[12]
It has also been demonstrated that patient with disseminated carcinoma had fewer macrophages whereas in localised carcinoma there were increased monocytic mobilisation.
Increased phagocytic activity in monocyte/macrophages is related to untreated hodgkin's disease.On the other hand decreased phagocytic activity is related to stage III and IV hodgkin's disease.[12]
There are also lysozyme secretion disorder in malignancy. Favourable clinical condition showed enhanced lysozyme secretion whereas depressed lysozyme secretion is related to poorer prognosis.
It has also been proved that presence of macrophages are more in non metastasizing tumour and less in metastasizing tumour.[12]
Alzheimer disease is also related to MPS disorder. Neurotoxicity in Alzheimer is related to higher brain A beta levels. Monocytes accumulate at sites of A-beta deposition is an initial attempt to clear these deposits and stop or delay their neurotoxic effects. Interaction of CCL2( A major monocyte chemokine), with its receptor CCR2 regulates mononuclear phagocyte accumulation and its clearance. CCR2 deficiency leads to lower mononuclear phagocyte accumulation as a result, higher brain A-beta levels and neurotoxicity.[13]

Conclusion:
This article has first, briefly gives a review and current concept on reticuloendothelial system and mononuclear phagocyte system.
In particular, the review pointed out the cells of mononuclear phagocyte system, how these are developed and its genetic control. It has also described the essential role of macrophages between health and disease.
Better understanding of mononuclear phagocyte system will provide us various scope of further investigation in the field of its clinical and basic research.

References
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