لخّصلي

Abstract:
Macrophages are a diverse phenotype of professional phagocytic cells derived from bone-marrow precursors and parent monocytes in the peripheral blood. They are essential for the maintenance and defense of host tissues, doing so by sensing and engulfing particulate matter and, when necessary, initiating a pro-inflammatory response. Playing such a vast number of roles in both health and disease, the activation phenotype of macrophages can vary greatly and is largely dependent on the surrounding microenvironment. These phenotypes can be mimicked in experimental macrophage models derived from monocytes and in conjunction with stimulatory factors, although given the complexity of in vivo tissue spaces these model cells are inherently imperfect. Furthermore, experimental observations generated in mice are not necessarily conserved in humans, which can hamper translational research.
Key words:
Monocytes Macrophages Origin Activation Differentiation Function
Introduction:
Macrophages are important cells of the immune system that are formed in response to an infection or accumulating damaged or dead cells. Macrophages are large, specialized cells that recognize, engulf and destroy target cells. The term macrophage is formed by the combination of the Greek terms "Makro" meaning big and "phagein" meaning eat.
Review of Literature
Macrophage Typing
According to the activation state and functions of macrophages, they can be divided into M1-type (classically activated macrophage) and M2-type (alternatively activated macrophage).
The role of M1 macrophages is to secrete pro-inflammatory cytokines and chemokines, present antigens, and thus participate in the positive immune response and function as an immune monitor. The main pro-inflammatory cytokines it produces are IL-6, IL-12 and TNF-alpha.
M2 macrophages mainly secrete Arginase-I, IL-10 and TGF-β and other anti-inflammatory cytokines, which have the function of reducing inflammation and contributing to tumor growth and Immunosuppressive function It plays an important role in wound healing and tissue repair.
In a word, macrophages are a "double-edged sword", which can not only stop the spread of cancer cells, but also help the growth and spread of cancer cells. M1 and M2 macrophages can also be converted to each other in a specific microenvironment.

Classification and Origins of Tissue Macrophages:
Macrophages are professional phagocytes involved in the recycling and clearance of erythrocytes during the steady state, the removal of apoptotic cells and cellular debris, tissue remodeling, and host responses to infectious disease. They are remarkably plastic cells that can rapidly shift their physiology in response to cues generated after injury or infection. The surrounding microenvironment largely determines the activation phenotype of recruited macrophages, which can most simply be classified as falling within a spectrum consisting of two opposing phenotypes: classically activated, or M1, macrophages (CAMs), and alternatively activated, or M2, macrophages (AAMs). Additionally, there are subsets of specialized resident macrophages whose phenotypes are uniquely adapted to their location, such as brain microglia, liver Kupffer cells, bone osteoclasts, and lung alveolar macrophages. These distinct cell types can also be skewed towards classical or alternative activation, although their differentiation in response to a given stimulus may not be analogous
Macrophage Function:
The macrophage is a fascinating cell type in that its primary role is maintaining homeostasis. This includes host defense against foreign invaders, the clearance of necrotic and apoptotic debris and tissue remodeling following injury. It performs these roles via four basic innate functions: sensing, chemotaxis, phagocytosis and repair, and adaptive stimulation. Although macrophages have the ability to promote adaptive immune responses, they are considered innate effector cells, since they do not require previous exposure to a given antigen to initiate a response.
Sensing
Macrophages use intracellular and cell-surface PRRs to sense their local environment. When bound to a given ligand, these receptors generate signals that direct the macrophage response. Unlike the antigen-specific receptor found on T and B lymphocytes
Chemotaxis
Upon sensing an antigen belonging to a potentially harmful foreigner invader, macrophages stimulate the expansion of activated T cells and secrete chemokines that function to recruit appropriate effector cells to aid in their neutralization and clearance. Classically activated macrophages, who play a dominant role in anti-bacterial defence and promoting Th1-type responses
Phagocytosis and Tissue Repair
To return a tissue to homeostasis after a disruptive event, the phagocytic clearance of damaged and redundant material is essential. Examples include inflammatory events triggered by infection or injury and physiological changes within the host (i.e. embryonic development and
postpartum mammary gland involution, during which a great deal of tissue remodeling occurs. Using cell-surface receptors to identify its targets, as described above, macrophages engulf unwanted material, sequestering it within a phagosome compartment. This compartment subsequently fuses with a lysosomal compartment, which contains a number of highly reactive and toxic molecules that facilitate the destruction of the phagosome contents. Returning host tissues to a homeostatic state also requires the repair and remodeling of the local environment. Returning host tissues to a homeostatic state also requires the repair and remodeling of the local environment. Alternatively, activated macrophages are primarily responsible for this task, promoting extracellular matrix remodeling, cell growth, collagen production, and angiogenesis.
Adaptive Stimulation
The phagocytosis and subsequent destruction of foreign material by macrophages also provide a means to generate antigenic peptide sequences for presentation to T lymphocytes by way of cell-surface MHC class II receptors. Given suitable additional signaling, IL-12 or IL-4 for example, this interaction will lead to the expansion of antigen specific T lymphocytes and thus promote an adaptive immune response. However, unlike dendritic cells, most tissue macrophages can only present antigen and stimulate the expansion of activated T lymphocytes.
Role in Pathogenesis and Disease:
Macrophages illustrate well the interplay between intrinsic cellular properties (especially genetically determined) and environmental influences, including infections, toxins, drugs and pollutants. Both contribute to the complex patterns of gene expression which underlie cellular responses such as growth, phagocytosis and endocytosis, adhesion, migration, secretion and cell–cell interactions (trophic or cytocidal). ‘Disease’ results from either a primary deficiency of macrophages, or a reaction to extracellular abnormalities, resulting in under- or overactivity, or dysregulation of homeostatic pathways. Macrophages may be absent, present at an inappropriate place and increased or decreased in number due to faulty production or survival. Abnormalities can arise from inappropriate differentiation, recruitment or activation. The role of macrophages in a disease process is easily missed in the absence of a single organ location, striking disease association or ready access to tissues, other than blood (where circulating monocytes are relatively infrequent and not representative of tissue populations). The mouse model has long been useful in identifying genes involved in macrophage function; however, recent advances in human genetics have identified a number of genes associated with primary immunodeficiencies or macrophage function disorders in humans. Large-scale genome-wide association studies have also been informative in detecting more effects of single nucleotide polymorphisms, especially in chronic diseases such as diabetes and atherosclerosis. Here we refer to selected examples of macrophage function disorders, with emphasis on genetic disorders, to illustrate their role in important diseases.
advances in human genetics have identified a number of genes associated with primary immunodeficiencies or Infectious disease
Tuberculosis has been a major human disease for thousands of years and thus there has been considerable
Chronic disease
Atherogenesis Monocytes are recruited relatively early and selectively to major arteries in response to local accumulation of lipoproteins, e.g. in hyperlipidemia. Production of oxygen metabolites may exacerbate lipoprotein oxidation and promote its uptake by macrophages via a range of scavenger receptors, resulting in foam-cell formation. Such macrophages can interact with local endothelium, smooth muscle cells and fibroblasts, as well as T lymphocytes to initiate and perpetuate a modified form of chronic inflammation resulting in atheroma formation. Cell death, growth and migration of smooth muscle cells can all follow, mediated by macrophage products. Obstructive lesions may be repaired by fibrous tissue, or exacerbated by clotting induced by macrophages (and platelets) and by plaque rupture induced by macrophage metalloproteinases. Macrophages can also contribute to weakening and rupture of arterial walls, as in aneurysm, and of the heart, after myocardial infarction as part of an immune or inflammatory process. See also: Ischemic Heart Disease; Lipoprotein Metabolism: Structure and Function; Ozone and Reactive Oxygen Species Although there is a strong environmental component to the development of heart disease, there is also ample evidence for a genetic contribution. Polymorphisms in genes expressed in macrophages such as those associated with cholesterol uptake and efflux (and thus foam-cell formation) have been implicated in development of chronic heart disease as have a number of other genes known to be expressed by macrophages, but without a clearly defined function. Inflammatory bowel disorders e.g. Crohn disease Cancer
Cancer
is increasingly viewed as having a modified inflammatory component, and as with many inflammatory diseases, macrophages can be present in high numbers. In mouse models in which macrophages are almost entirely ablated due to a loss of function mutation in the gene encoding colony-stimulating factor 1 (CSF-1), tumor progression is stalled and metastasis ablated. Indeed, in human patients, a high density of tumor-associated macrophages indicates a poor prognosis. Macrophages are associated with even early stage tumors and their presence is essential for such processes as angiogenesis, extracellular-matrix breakdown and remodeling (which is required for subsequent motility) and intravasation. In cases where chronic inflammation is believed to be involved in the etiology of cancer, macrophages may contribute to malignancy by releasing DNA-damaging free radicals in addition to a host of growth and proliferation factors which may contribute to uncontrolled or dysregulated growth. In other experimental models the cancerous cells themselves recruit macrophages by secreting chemotactic and growth factors. Once recruited, macrophages appear to be strongly associated with hypoxia, angiogenesis and vascularization of the solid tumor, a process that is essential for tumor cell survival and is thus a target for drug development. The final and mostharmful stage in cancer progression is metastasis, which again, is a macrophage-associated process. Macrophages are associated with regions of basement membrane destruction, an essential pre-requisite for metastasis and through a complicated interplay between chemokines and growth factors produced by both the cancer cells and the macrophages contribute to intravasation. Although it is not entirely clear how macrophages contribute to seeding tumor cells at distant sites, in mouse models in which they are ablated, seeding is decreased (Candelas and Pollard, 2006).