Editing Macrophage (section)

==== Subtypes ====
{{multiple image
   | direction = horizontal
   | total_width = 300
   | footer    = Pigmented macrophages can be classified by the pigment type, such as for [[alveolar macrophages]] shown above (white arrows). A "siderophage" contains [[hemosiderin]] (also shown by black arrow in left image), while anthracotic macrophages result from coal dust inhalation (and also long-term air pollution).<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| vauthors = Cotran RS, Kumar V, Collins T | publisher=W.B Saunders Company| location=Philadelphia| isbn=978-0-7216-7335-6| year=1999}}</ref> [[H&E stain]].
   | image1    =Histopathology of siderophage in chronic pulmonary congestion.jpg
   | caption1  =[[Siderophage]]
   | image2    =Histopathology of anthracotic macrophage in lung, annotated.jpg
   | caption2  =[[Anthracosis|Anthracotic]] macrophage
}}

There are several activated forms of macrophages.<ref name="Mosser-2008" /> In spite of a spectrum of ways to activate macrophages, there are two main groups designated '''M1''' and '''M2'''. M1 macrophages: as mentioned earlier (previously referred to as classically activated macrophages),<ref>{{cite journal|title=The lymphocyte story|url=https://www.newscientist.com/channel/health/hiv/mg11716050.100|journal=New Scientist|issue=1605|access-date=2007-09-13}}</ref> M1 "killer" macrophages are activated by [[Lipopolysaccharide|LPS]] and [[Interferon-gamma|IFN-gamma]], and secrete high levels of [[Interleukin 12|IL-12]] and low levels of [[Interleukin 10|IL-10]]. M1 macrophages have pro-inflammatory, bactericidal, and phagocytic functions.<ref name="MH1">{{cite journal | vauthors = Hesketh M, Sahin KB, West ZE, Murray RZ | title = Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing | journal = International Journal of Molecular Sciences | volume = 18 | issue = 7 | pages = 1545 | date = July 2017 | pmid = 28714933 | pmc = 5536033 | doi = 10.3390/ijms18071545 | doi-access = free }}</ref> In contrast, the M2 "repair" designation (also referred to as alternatively activated macrophages) broadly refers to macrophages that function in constructive processes like wound healing and tissue repair, and those that turn off damaging immune system activation by producing anti-inflammatory cytokines like [[Interleukin 10|IL-10]]. M2 is the phenotype of resident tissue macrophages, and can be further elevated by [[Interleukin 4|IL-4]]. M2 macrophages produce high levels of IL-10, [[Transforming growth factor beta|TGF-beta]] and low levels of IL-12. Tumor-associated macrophages are mainly of the M2 phenotype, and seem to actively promote tumor growth.<ref>{{cite journal | vauthors = Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A | title = Tumor associated macrophages and neutrophils in tumor progression | journal = Journal of Cellular Physiology | volume = 228 | issue = 7 | pages = 1404–1412 | date = July 2013 | pmid = 23065796 | doi = 10.1002/jcp.24260 | s2cid = 41189572 }}</ref>

Macrophages exist in a variety of phenotypes which are determined by the role they play in wound maturation. Phenotypes can be predominantly separated into two major categories; M1 and M2. M1 macrophages are the dominating phenotype observed in the early stages of inflammation and are activated by four key mediators: interferon-γ (IFN-γ), tumor necrosis factor (TNF), and damage associated molecular patterns (DAMPs). These mediator molecules create a pro-inflammatory response that in return produce pro-inflammatory cytokines like Interleukin-6 and TNF. Unlike M1 macrophages, M2 macrophages secrete an anti-inflammatory response via the addition of Interleukin-4 or Interleukin-13. They also play a role in wound healing and are needed for revascularization and reepithelialization. M2 macrophages are divided into four major types based on their roles: M2a, M2b, M2c, and M2d. How M2 phenotypes are determined is still up for discussion but studies have shown that their environment allows them to adjust to whichever phenotype is most appropriate to efficiently heal the wound.<ref name="MH1" />

M2 macrophages are needed for vascular stability. They produce [[Vascular endothelial growth factor A|vascular endothelial growth factor-A]] and [[TGF beta 1|TGF-β1]].<ref name=MH1/> There is a phenotype shift from M1 to M2 macrophages in acute wounds, however this shift is impaired for chronic wounds. This dysregulation results in insufficient M2 macrophages and its corresponding growth factors that aid in wound repair. With a lack of these growth factors/anti-inflammatory cytokines and an overabundance of pro-inflammatory cytokines from M1 macrophages chronic wounds are unable to heal in a timely manner. Normally, after neutrophils eat debris/pathogens they perform apoptosis and are removed. At this point, inflammation is not needed and M1 undergoes a switch to M2 (anti-inflammatory). However, dysregulation occurs as the M1 macrophages are unable/do not phagocytose neutrophils that have undergone apoptosis leading to increased macrophage migration and inflammation.<ref name=MH1/>

Both M1 and M2 macrophages play a role in promotion of [[atherosclerosis]]. M1 macrophages promote atherosclerosis by inflammation. M2 macrophages can remove cholesterol from blood vessels, but when the cholesterol is oxidized, the M2 macrophages become [[Apoptosis|apoptotic]] [[foam cells]] contributing to the [[Atheroma|atheromatous plaque]] of atherosclerosis.<ref name="pmid20376052">{{cite journal | vauthors = Hotamisligil GS | title = Endoplasmic reticulum stress and atherosclerosis | journal = Nature Medicine | volume = 16 | issue = 4 | pages = 396–399 | date = April 2010 | pmid = 20376052 | pmc = 2897068 | doi = 10.1038/nm0410-396 }}</ref><ref name="pmid22356914">{{cite journal | vauthors = Oh J, Riek AE, Weng S, Petty M, Kim D, Colonna M, Cella M, Bernal-Mizrachi C | title = Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation | journal = The Journal of Biological Chemistry | volume = 287 | issue = 15 | pages = 11629–11641 | date = April 2012 | pmid = 22356914 | pmc = 3320912 | doi = 10.1074/jbc.M111.338673 | doi-access = free }}</ref>