species). in order to minimize the possibility of becoming the host of an intracellular bacteria, macrophages have evolved defense mechanisms such as induction of nitric oxide and reactive oxygen intermediates, which are toxic to microbes. macrophages have also evolved the ability to restrict the microbe's nutrient supply and induce autophagy. tuberculosis once engulfed by a macrophage, the causative agent of tuberculosis, mycobacterium tuberculosis, avoids cellular defenses and uses the cell to replicate. recent evidence suggests that in response to the pulmonary infection of mycobacterium tuberculosis, the peripheral macrophages matures into m1 phenotype. macrophage m1 phenotype is characterized by increased secretion of pro-inflammatory cytokines (il-1β, tnf-α, and il-6) and increased glycolytic activities essential for clearance of infection. leishmaniasis upon phagocytosis by a macrophage, the leishmania parasite finds itself in a phagocytic vacuole. under normal circumstances, this phagocytic vacuole would develop into a lysosome and its contents would be digested. leishmania alter this process and avoid being destroyed; instead, they make a home inside the vacuole. chikungunya infection of macrophages in joints is associated with local inflammation during and after the acute phase of chikungunya (caused by chikv or chikungunya virus). others adenovirus (most common cause of pink eye) can remain latent in a host macrophage, with continued viral shedding 6–18 months after initial infection. brucella spp. can remain latent in a macrophage via inhibition of phagosome–lysosome fusion; causes brucellosis (undulant fever). legionella pneumophila, the causative agent of legionnaires' disease, also establishes residence within macrophages. heart disease macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis. focal recruitment of macrophages occurs after the onset of acute myocardial infarction. these macrophages function to remove debris, apoptotic cells and to prepare for tissue regeneration. macrophages protect against ischemia-induced ventricular tachycardia in hypokalemic mice. 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. hiv can enter the macrophage through binding of gp120 to cd4 and second membrane receptor, ccr5 (a chemokine receptor). both circulating monocytes and macrophages serve as a reservoir for the virus. macrophages are better able to resist infection by hiv-1 than cd4+ t cells, although susceptibility to hiv infection differs among macrophage subtypes. cancer macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells. attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation. inflammatory compounds such as tumor necrosis factor (tnf)-alpha released by the macrophages activate the gene switch nuclear factor-kappa b. nf-κb then enters the nucleus of a tumor cell and turns on production of proteins that stop apoptosis and promote cell proliferation and inflammation. moreover, macrophages serve as a source for many pro-angiogenic factors including vascular endothelial factor (vegf), tumor necrosis factor-alpha (tnf-alpha), macrophage colony-stimulating factor (m-csf/csf1) and il-1 and il-6 contributing further to the tumor growth. macrophages have been shown to infiltrate a number of tumors. their number correlates with poor prognosis in certain cancers including cancers of breast, cervix, bladder, brain and prostate. tumor-associated macrophages (tams) are thought to acquire an m2 phenotype, contributing to tumor growth and progression. some tumors can also produce factors, including m-csf/csf1, mcp-1/ccl2 and angiotensin ii, that trigger the amplification and mobilization of macrophages in tumors. research in various study models suggests that macrophages can sometimes acquire anti-tumor functions. for example, macrophages may have cytotoxic activity to kill tumor cells directly; also the co-operation of t-cells and macrophages is important to suppress tumors. this co-operation involves not only the direct contact of t-cell and macrophage, with antigen presentation, but also includes the secretion of adequate combinations of cytokines, which enhance t-cell antitumor activity. recent study findings suggest that by forcing ifn-α expression in tumor-infiltrating macrophages, it is possible to blunt their innate protumoral activity and reprogram the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity. additionally, subcapsular sinus macrophages in tumor-draining lymph nodes can suppress cancer progression by containing the spread of tumor-derived materials. cancer therapy experimental studies indicate that macrophages can affect all therapeutic modalities, including surgery, chemotherapy, radiotherapy, immunotherapy and targeted therapy. macrophages can influence treatment outcomes both positively and negatively. macrophages can be protective in different ways: they can remove dead tumor cells (in a process called phagocytosis) following treatments that kill these cells; they can serve as drug depots for some anticancer drugs; they can also be activated by some therapies to promote antitumor immunity. macrophages can also be deleterious in several ways: for example they can suppress various chemotherapies, radiotherapies and immunotherapies. because macrophages can regulate tumor progression, therapeutic strategies to reduce the number of these cells, or to manipulate their phenotypes, are currently being tested in cancer patients. however, macrophages are also involved in antibody mediated cytotoxicity (adcc) and this mechanism has been proposed to be important for certain cancer immunotherapy antibodies. obesity it has been observed that increased number of pro-inflammatory macrophages within obese adipose tissue contributes to obesity complications including insulin resistance and diabetes type 2. the modulation of the inflammatory state of adipose tissue macrophages has therefore been considered a possible therapeutic target to treat obesity-related diseases. although adipose tissue macrophages are subject to anti-inflammatory homeostatic control by sympathetic innervation, experiments using adrb2 gene knockout mice indicate that this effect is indirectly exerted through the modulation of adipocyte function, and not through direct beta-2 adrenergic receptor activation, suggesting that adrenergic stimulation of macrophages may be insufficient to impact adipose tissue inflammation or function in obesity. within the fat (adipose) tissue of ccr2 deficient mice, there is an increased number of eosinophils, greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. furthermore, this effect was exaggerated when the mice became obese from a high fat diet. this is partially caused by a phenotype switch of macrophages induced by necrosis of fat cells (adipocytes). in an obese individual some adipocytes burst and undergo necrotic death, which causes the residential m2 macrophages to switch to m1 phenotype. this is one of the causes of a low-grade systemic chronic inflammatory state associated with obesity. intestinal macrophages though very similar in structure to tissue macrophages, intestinal macrophages have evolved specific characteristics and functions given their natural environment, which is in the digestive tract. macrophages and intestinal macrophages have high plasticity causing their phenotype to be altered by their environments. like macrophages, intestinal macrophages are differentiated monocytes, though intestinal macrophages have to coexist with the microbiome in the intestines. this is a challenge considering the bacteria found in the gut are not recognized as "self" and could be potential targets for phagocytosis by the macrophage. to prevent the destruction of the gut bacteria, intestinal macrophages have developed key differences compared to other macrophages. primarily, intestinal macrophages do not induce inflammatory responses. whereas tissue macrophages release various inflammatory cytokines, such as il-1, il-6 and tnf-α, intestinal macrophages do not produce or secrete inflammatory cytokines. this change is directly caused by the intestinal macrophages environment. surrounding intestinal epithelial cells release tgf-β, which induces the change from proinflammatory macrophage to noninflammatory macrophage. even though the inflammatory response is downregulated in intestinal macrophages, phagocytosis is still carried out. there is no drop off in phagocytosis efficiency as intestinal macrophages are able to effectively phagocytize the bacteria,s. typhimurium and e. coli, but intestinal macrophages still do not release cytokines, even after phagocytosis. also, intestinal macrophages do not express lipopolysaccharide (lps), iga, or igg receptors. the lack of lps receptors is important for the gut as the intestinal macrophages do not detect the microbe-associated molecular patterns (mamps/pamps) of the intestinal microbiome. nor do they express il-2 and il-3 growth factor receptors. role in disease intestinal macrophages have been shown to play a role in inflammatory bowel disease (ibd), such as crohn's disease (cd) and ulcerative colitis (uc). in a healthy gut, intestinal macrophages limit the inflammatory response in the gut, but in a disease-state, intestinal macrophage numbers and diversity are altered. this leads to inflammation of the gut and disease symptoms of ibd. intestinal macrophages are critical in maintaining gut homeostasis. the presence of inflammation or pathogen alters this homeostasis, and concurrently alters the intestinal macrophages. there has yet to be a determined mechanism for the alteration of the intestinal macrophages by recruitment of new monocytes or changes in the already present intestinal macrophages. additionally, a new study reveals macrophages limit iron access to bacteria by releasing extracellular vesicles, improving sepsis outcomes. history macrophages were first discovered late in the 19th century by élie metchnikoff.