THE MACROPHAGE

Macrophages are white blood cells produced by the differentiation of monocytes in tissues. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense (innate immunity) as well as help initiate specific defense mechanisms (adaptive immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogens, either as stationary or as mobile cells. They also stimulate lymphocytes and other immune cells to respond to pathogens.

Macrophages are important in the regulation of immune responses. They are often referred to as scavengers or antigen-presenting cells (APC) because they pick up and ingest foreign materials and present these antigens to other cells of the immune system such as T cells and B cells. This is one of the important first steps in the initiation of an immune response. Stimulated macrophages exhibit increased levels of phagocytosis and are also secretory.

When a leukocyte enters damaged tissue through the endothelium of a blood vessel, it undergoes a series of changes to become a macrophage. Monocytes are attracted to a damaged site by chemical substances through chemotaxis, triggered by a range of stimuli including damaged cells, pathogens and cytokines released by macrophages already at the site. At some sites such as the testis, macrophages have been shown to populate the organ through proliferation. Unlike short-lived neutrophils, macrophages survive longer in the body up to a maximum of several months.

One important role of the macrophage is the removal of necrotic cellular debris in the lungs. Removing dead cell material is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophil granulocytes, which are ingested by macrophages if they come of age. The removal of necrotic tissue is, to a greater extent, handled by fixed macrophages, which will stay at strategic locations such as the lungs, liver, neural tissue, bone, spleen and connective tissue, ingesting foreign materials such as pathogens and recruiting additional macrophages if needed. When a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome, which then fuses with a lysosome. Within the phagolysosome, enzymes and toxic peroxides digest the pathogen. However, some bacteria, such as Mycobacterium tuberculosis, have become resistant to these methods of digestion. Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds.

Macrophages are versatile cells that play many roles. As scavengers, they rid the body of worn-out cells and other debris. Along with dendritic cells, they are foremost among the cells that "present" antigen, a crucial role in initiating an immune response. As secretory cells, monocytes and macrophages are vital to the regulation of immune responses and the development of inflammation; they produce a wide array of powerful chemical substances (monokines) including enzymes, complement proteins, and regulatory factors such as interleukin-1. At the same time, they carry receptors for lymphokines that allow them to be "activated" into single-minded pursuit of microbes and tumour cells.

After digesting a pathogen, a macrophage will present the antigen (a molecule, most often a protein found on the surface of the pathogen, used by the immune system for identification) of the pathogen to the corresponding helper T cell. The presentation is done by integrating it into the cell membrane and displaying it attached to an MHC class II molecule, indicating to other white blood cells that the macrophage is not a pathogen, despite having antigens on its surface.

Eventually, the antigen presentation results in the production of antibodies that attach to the antigens of pathogens, making them easier for macrophages to adhere to with their cell membrane and phagocytose. In some cases, pathogens are very resistant to adhesion by the macrophages.

The antigen presentation on the surface of infected macrophages (in the context of MHC class II) in a lymph node stimulates TH1 (type 1 helper T cells) to proliferate (mainly due to IL-12 secretion from the macrophage). When a B-cell in the lymph node recognizes the same unprocessed surface antigen on the bacterium with its surface bound antibody, the antigen is endocytosed and processed. The processed antigen is then presented in MHCII on the surface of the B-cell. TH1 receptor that has proliferated recognizes the antigen-MHCII complex (with co-stimulatory factors- CD40 and CD40L) and causes the B-cell to produce antibodies that help opsonisation of the antigen so that the bacteria can be better cleared by phagocytes.

Macrophages provide yet another line of defense against tumor cells and somatic cells infected with fungus or parasites. Once a T cell has recognized its particular antigen on the surface of an aberrant cell, the T cell becomes an activated effector cell, chemical mediators known as lymphokines that stimulate macrophages into a more aggressive form. These activated macrophages can then engulf and digest affected cells much more readily. The macrophage does not generate a response specific for an antigen, but attacks the cells present in the local area in which it was activated.

A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of dust is likely to occur. Each type of macrophage, determined by its location, has a specific name:

Name of cell Location
Alveolar macrophages pulmonary alveolus
Histiocytes connective tissue
Kupffer cells liver
Microglia neural tissue
Epithelioid cells granuomas
Osteoclasts bone
Sinusoidal lining cells spleen

Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system. For example, they participate in the formation of granulomas, inflammatory lesions that may be caused by a large number of diseases. Some disorders, mostly rare, of ineffective phagocytosis and macrophage function have been described, for example.

Tuberculosis

- Once engulfed by a macrophage the causititve agent of tuberculosis, Mycobacterium tuberculosis avoids cellular defenses and uses the cell to replicate.

Heart Disease

Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis.

HIV infection

- Macrophages also play a role in Human Immunodeficiency Virus (HIV) infection. Like T cells, macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body.

Cancer

- Macrophages are believed to help cancer cells proliferate as well. They are attracted to oxygen-starved (hypoxic) tumour cells and promote chronic inflammation. Inflammatory compounds such as Tumor necrosis factor (TNF) released by the macrophage activates the gene switch nuclear factor-kappa B. NF-κB then enters the nucleus of a tumour cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation.



Traditional and alternate Macrophage Activation?

Macrophage effector function significantly influences the quality, duration, and magnitude of most inflammatory reactions. Traditionally, macrophages have been described as antigen-presenting phagocytes that secrete pro-inflammatory and antimicrobial mediators.1 Mounting evidence, however, describes a more complex model involving multiple macrophage phenotypes carrying out differential functions and eliciting divergent effects on surrounding cells and tissues. Stein et al. were the first to describe "alternatively" activated macrophages as having a phenotype distinct from what are now called "classically" activated macro-phages.2 From this seminal observation, a model of two major macrophage classes has developed. Classically activated macrophages exhibit a Th1-like phenotype, promoting inflammation, extracellular matrix (ECM) destruction, and apoptosis, while alternatively activated macrophages display a Th2-like phenotype, promoting ECM construction, cell proliferation, and angiogenesis. Although both phenotypes are important components of both the innate and adaptive immune systems, the classically activated macrophage tends to elicit chronic inflammation and tissue injury whereas the alternatively activated macrophage tends to resolve inflammation and facilitate wound healing.

Differentiation of classically activated macrophages requires a priming signal in the form of IFN-α7 via the IFN-α R.8 When the primed macrophage subsequently encounters an appropriate stimulus, such as bacterial LPS, it becomes classically activated. LPS is first bound by soluble LBP and then by either soluble or membrane-bound CD14. CD14 delivers LPS to the LPS recognition complex,9 which consists of at least TLR410 and MD-2.11 Pathogens and pathogen components are subsequently taken up by phagocytosis12 and delivered to lysosomes where they are exposed to a variety of degradation enzymes including several Cathepsin cysteine proteases.13 Suitable antigens are processed and loaded onto MHC class II molecules in late endocytic compartments and antigen/MHCII complexes as well as co-stimulatory B7 family members are presented to T cells.14

These events are followed closely by a significant change in cellular morph-ology and a dramatic alteration in the secretory profile of the cell. A variety of chemokines including IL-8/CXCL8, IP-10/CXCL10, MIP-1a/CCL3, MIP-1ß/CCL4, and RANTES/CCL5, are released as chemoattractants for neutrophils, immature dendritic cells, natural killer cells, and activated T cells.15 Further, several pro-inflammatory cytokines are released including IL-1ß/IL-1F2, IL-6, and TNF-a/TNFSF1A.3-6 TNF-a also contributes to the pro-apoptotic activity of the classically activated macrophage.16-18 TNF-a is accompanied by Fas Ligand/TNFSF6 secretion16 and NO release as a result of iNOS upregulation.19-22 In addition, the classically activated macrophage releases proteolytic enzymes including MMP-1, -2, -7, -9, and -12, which degrade Collagen, Elastin, Fibronectin, and other ECM components.23-25

While the release of these molecules is important for host defense and direction of the adaptive immune system, when uncontrolled they can levy sig-nificant collateral damage on the microenvironment. By eliciting massive leukocyte infiltration and flooding the surrounding tissue with inflammatory mediators, pro-apoptotic factors, and matrix degrading proteases, the classically activated macrophage is capable of dismantling tissues to the point of inflicting serious injury. Tissue destruction perpetrated by chronic inflammation has been associated with the development of tumors, type 1 autoimmune diseases, and glomerulonephritis among other pathologies.4,6

Alternatively Activated Macrophages

Differentiation of alternatively activated macrophages does not require any priming. IL-42 and/or IL-1326 can act as sufficient stimuli. The binding of these factors to their respective receptors is followed by fluid-phase pinocytosis of soluble antigen.27-29 Soluble antigen is then loaded onto MHC class II molecules and antigen/MHCII complexes and co-stimulatory B7 family members are subsequently displayed to T cells.14

Similar to the classically activated macrophage, the alternatively activated macrophage changes its cellular morphology and secretory pattern as a result of appropriate stimulation. Leukocytes are attracted by the macrophage via its release of chemokines including MDC/CCL22,30,31 PARC/CCL18,32,33 and TARC/CCL17.31 Inflammation is counteracted by the release of factors such as IL-1ra/IL-1F3,34 Ym1, Ym2, RELMa,35,36 IL-10,6 and TGF-ß. TGF-ß also functions indirectly to promote ECM building by inducing nearby fibroblasts to produce ECM components.18 The alternatively activated macrophage itself secretes the ECM components, Fibronectin and bIG-H3,37 the ECM cross-linking enzyme, Trans-glutaminase,38 and Osteopontin, which is involved in cell adhesion to the ECM.39

In addition, alternatively activated macrophages upregulate the enzyme Arginase I, which is involved in proline as well as polyamine biosynthesis. Proline promotes ECM construction while polyamines are involved in cell proliferation.19 Other factors secreted by the alternatively activated macrophage that promote cell proliferation include PDGF, IGF, and TGF-ß.18,40 These factors, along with FGF basic, TGF-a, and VEGF, also participate in angiogenesis.40,41

The molecules secreted by the alternatively activated macrophage work toward resolution of inflammation and promotion of wound repair due to their anti-inflammatory, fibrotic, proliferative, and angiogenic activities. This macro-phage is also especially efficient at combating parasitic infections such as Schistosomiasis. In addition to its beneficial activities, the alternatively activated macrophage has been implicated in several pathologies, the most prominent of which are allergy and asthma.3,4

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