macrophage macrophage macrophages (abbreviated as mφ, mφ or mp) (greek: large eaters, from greek μακρός (makrós) = large, φαγεῖν (phagein) = to eat) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. this process is called phagocytosis, which acts to defend the host against infection and injury. macrophagecytology of a macrophage with typical features. wright stain.detailspronunciation/ˈmakrə(ʊ)feɪdʒ/systemimmune systemfunctionphagocytosisidentifierslatinmacrophagocytusacronym(s)mφ, mφmeshd008264thh2.00.03.0.01007 fma63261anatomical terms of microanatomy macrophages are found in essentially all tissues, where they patrol for potential pathogens by amoeboid movement. they take various forms (with various names) throughout the body (e.g., histiocytes, kupffer cells, alveolar macrophages, microglia, and others), but all are part of the mononuclear phagocyte system. besides phagocytosis, they play a critical role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes. for example, they are important as antigen presenters to t cells. in humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections. beyond increasing inflammation and stimulating the immune system, macrophages also play an important anti-inflammatory role and can decrease immune reactions through the release of cytokines. macrophages that encourage inflammation are called m1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called m2 macrophages. this difference is reflected in their metabolism; m1 macrophages have the unique ability to metabolize arginine to the "killer" molecule nitric oxide, whereas m2 macrophages have the unique ability to metabolize arginine to the "repair" molecule ornithine. however, this dichotomy has been recently questioned as further complexity has been discovered. human macrophages are about 21 micrometres (0.00083 in) in diameter and are produced by the differentiation of monocytes in tissues. they can be identified using flow cytometry or immunohistochemical staining by their specific expression of proteins such as cd14, cd40, cd11b, cd64, f4/80 (mice)/emr1 (human), lysozyme m, mac-1/mac-3 and cd68. macrophages were first discovered and named by élie metchnikoff, a russian zoologist, in 1884. structure types main article: mononuclear phagocyte system "macrophage activation" redirects here. for the signal, see macrophage-activating factor. for the disease syndrome, see macrophage activation syndrome. drawing of a macrophage when fixed and stained by giemsa dye a majority of macrophages are stationed at strategic points where microbial invasion or accumulation of foreign particles is likely to occur. these cells together as a group are known as the mononuclear phagocyte system and were previously known as the reticuloendothelial system. each type of macrophage, determined by its location, has a specific name: cell nameanatomical location adipose tissue macrophagesadipose tissue (fat) monocytesbone marrow / blood kupffer cellsliver sinus histiocyteslymph nodes alveolar macrophages (dust cells)pulmonary alveoli tissue macrophages (histiocytes) leading to giant cellsconnective tissue microgliacentral nervous system hofbauer cellsplacenta intraglomerular mesangial cellskidney osteoclasts bone langerhans cellsskin epithelioid cellsgranulomas red pulp macrophages (sinusoidal lining cells)red pulp of spleen peritoneal macrophagesperitoneal cavity lysomacpeyer's patch perivascular macrophagesclosely associated with blood vessels investigations concerning kupffer cells are hampered because in humans, kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies. from rats and mice, they are difficult to isolate, and after purification, only approximately 5 million cells can be obtained from one mouse. macrophages can express paracrine functions within organs that are specific to the function of that organ. in the testis, for example, macrophages have been shown to be able to interact with leydig cells by secreting 25-hydroxycholesterol, an oxysterol that can be converted to testosterone by neighbouring leydig cells. also, testicular macrophages may participate in creating an immune privileged environment in the testis, and in mediating infertility during inflammation of the testis. cardiac resident macrophages participate in electrical conduction via gap junction communication with cardiac myocytes. macrophages can be classified on basis of the fundamental function and activation. according to this grouping there are classically activated (m1) macrophages, wound-healing macrophages (also known as alternatively-activated (m2) macrophages), and regulatory macrophages (mregs). development macrophages that reside in adult healthy tissues either derive from circulating monocytes or are established before birth and then maintained during adult life independently of monocytes. by contrast, most of the macrophages that accumulate at diseased sites typically derive from circulating monocytes. leukocyte extravasation describes monocyte entry into damaged tissue through the endothelium of blood vessels as they become macrophages. 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 several months. function steps of a macrophage ingesting a pathogen: a. ingestion through phagocytosis, a phagosome is formedb. the fusion of lysosomes with the phagosome creates a phagolysosome; the pathogen is broken down by enzymesc. waste material is expelled or assimilated (the latter not pictured) parts:1. pathogens2. phagosome3. lysosomes4. waste material5. cytoplasm6. cell membrane phagocytosis macrophages are professional phagocytes and are highly specialized in removal of dying or dead cells and cellular debris. this role is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophils, which are ingested by macrophages if they come of age (see cd31 for a description of this process). the neutrophils are at first attracted to a site, where they perform their function and die, before they or their neutrophil extracellular traps are phagocytized by the macrophages. when at the site, the first wave of neutrophils, after the process of aging and after the first 48 hours, stimulate the appearance of the macrophages whereby these macrophages will then ingest the aged neutrophils. the removal of dying cells 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. typhoidal salmonellae induce their own phagocytosis by host macrophages in vivo, and inhibit digestion by lysosomal action, thereby using macrophages for their own replication and causing macrophage apoptosis. macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds. role in innate immune response when a pathogen invades, tissue resident macrophages are among the first cells to respond. two of the main roles of the tissue resident macrophages are to phagocytose incoming antigen and to secrete proinflammatory cytokines that induce inflammation and recruit other immune cells to the site. phagocytosis of pathogens macrophages can internalize antigens through receptor-mediated phagocytosis. macrophages have a wide variety of pattern recognition receptors (prrs) that can recognize microbe-associated molecular patterns (mamps) from pathogens. many prrs, such as toll-like receptors (tlrs), scavenger receptors (srs), c-type lectin receptors, among others, recognize pathogens for phagocytosis. macrophages can also recognize pathogens for phagocytosis indirectly through opsonins, which are molecules that attach to pathogens and mark them for phagocytosis. opsonins can cause a stronger adhesion between the macrophage and pathogen during phagocytosis, hence opsonins tend to enhance macrophages’ phagocytic activity. both complement proteins and antibodies can bind to antigens and opsonize them. macrophages have complement receptor 1 (cr1) and 3 (cr3) that recognize pathogen-bound complement proteins c3b and ic3b, respectively, as well as fragment crystallizable γ receptors (fcγrs) that recognize the fragment crystallizable (fc) region of antigen-bound immunoglobulin g (igg) antibodies. when phagocytosing and digesting pathogens, macrophages go through a respiratory burst where more oxygen is consumed to supply the energy required for producing reactive oxygen species (ros) and other antimicrobial molecules that digest the consumed pathogens. cytokine secretion recognition of mamps by prrs can activate tissue resident macrophages to secrete proinflammatory cytokines that recruit other immune cells. among the prrs, tlrs play a major role in signal transduction leading to cytokine production. the binding of mamps to tlr triggers a series of downstream events that eventually activates transcription factor nf-κb and results in transcription of the genes for several proinflammatory cytokines, including il-1β, il-6, tnf-α, il-12b, and type i interferons such as ifn-α and ifn-β. systemically, il-1β, il-6, and tnf-α induce fever and initiate the acute phase response in which the liver secretes acute phase proteins. locally, il-1β and tnf-α cause vasodilation, where the gaps between blood vessel epithelial cells widen, and upregulation of cell surface adhesion molecules on epithelial cells to induce leukocyte extravasation. neutrophils are among the first immune cells recruited by macrophages to exit the blood via extravasation and arrive at the infection site. macrophages secrete many chemokines such as cxcl1, cxcl2, and cxcl8 (il-8) that attract neutrophils to the site of infection. after neutrophils have finished phagocytosing and clearing the antigen at the end of the immune response, they undergo apoptosis, and macrophages are recruited from blood monocytes to help clear apoptotic debris. macrophages also recruit other immune cells such as monocytes, dendritic cells, natural killer cells, basophils, eosinophils, and t cells through chemokines such as ccl2, ccl4, ccl5, cxcl8, cxcl9, cxcl10, and cxcl11. along with dendritic cells, macrophages help activate natural killer (nk) cells through secretion of type i interferons (ifn-α and ifn-β) and il-12. il-12 acts with il-18 to stimulate the production of proinflammatory cytokine interferon gamma (ifn-γ) by nk cells, which serves as an important source of ifn-γ before the adaptive immune system is activated. ifn-γ enhances the innate immune response by inducing a more aggressive phenotype in macrophages, allowing macrophages to more efficiently kill pathogens. some of the t cell chemoattractants secreted by macrophages include ccl5, cxcl9, cxcl10, and cxcl11. role in adaptive immunity a macrophage stretching its "arms" (filopodia) to engulf two particles, possibly pathogens, in a mouse (trypan blue exclusion staining). interactions with cd4+ t helper cells macrophages are professional antigen presenting cells (apc), meaning they can present peptides from phagocytosed antigens on major histocompatibility complex (mhc) ii molecules on their cell surface for t helper cells. macrophages are not primary activators of naïve t helper cells that have never been previously activated since tissue resident macrophages do not travel to the lymph nodes where naïve t helper cells reside. although macrophages are also found in secondary lymphoid organs like the lymph nodes, they do not reside in t cell zones and are not effective at activating naïve t helper cells. the macrophages in lymphoid tissues are more involved in ingesting antigens and preventing them from entering the blood, as well as taking up debris from apoptotic lymphocytes. therefore, macrophages interact mostly with previously activated t helper cells that have left the lymph node and arrived at the site of infection or with tissue resident memory t cells. macrophages supply both signals required for t helper cell activation: 1) macrophages present antigen peptide-bound mhc class ii molecule to be recognized by the corresponding t cell receptor (tcr), and 2) recognition of pathogens by prrs induce macrophages to upregulate the co-stimulatory molecules cd80 and cd86 (also known as b7) that binds to cd28 on t helper cells to supply the co-stimulatory signal. these interactions allow t helper cells to achieve full effector function and provide t helper cells with continued survival and differentiation signals preventing them from undergoing apoptosis due to lack of tcr signaling. for example, il-2 signaling in t cells upregulates the expression of anti-apoptotic protein bcl-2, but t cell production of il-2 and the high-affinity il-2 receptor il-2ra both require continued signal from tcr recognition of mhc-bound antigen. activation macrophages can achieve different activation phenotypes through interactions with different subsets of t helper cells, such as th1 and th2. although there is a broad spectrum of macrophage activation phenotypes, there are two major phenotypes that are commonly acknowledged. they are the classically activated macrophages, or m1 macrophages, and the alternatively activated macrophages, or m2 macrophages. m1 macrophages are proinflammatory, while m2 macrophages are mostly anti-inflammatory. classical th1 cells play an important role in classical macrophage activation as part of type 1 immune response against intracellular pathogens (such