Editing Macrophage (section)

=== Role in adaptive immunity ===
[[File:Macrophage.jpg|thumb|A macrophage stretching its "arms" ([[filopodia]])<ref name="Kress">{{cite journal | vauthors = Kress H, Stelzer EH, Holzer D, Buss F, Griffiths G, Rohrbach A | title = Filopodia act as phagocytic tentacles and pull with discrete steps and a load-dependent velocity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 28 | pages = 11633–11638 | date = July 2007 | pmid = 17620618 | pmc = 1913848 | doi = 10.1073/pnas.0702449104 | doi-access = free | bibcode = 2007PNAS..10411633K }}</ref> to engulf two particles, possibly pathogens, in a mouse ([[Trypan blue|trypan blue exclusion]] staining).]]

==== Interactions with CD4<sup>+</sup> 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.<ref name="Guerriero-2019">{{cite journal | vauthors = Guerriero JL | title = Macrophages: Their Untold Story in T Cell Activation and Function | journal = International Review of Cell and Molecular Biology | volume = 342 | pages = 73–93 | date = 2019 | pmid = 30635094 | doi = 10.1016/bs.ircmb.2018.07.001 | publisher = Elsevier | isbn = 978-0-12-815381-9 }}</ref> 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.<ref name="Itano-2003">{{cite journal | vauthors = Itano AA, Jenkins MK | title = Antigen presentation to naive CD4 T cells in the lymph node | journal = Nature Immunology | volume = 4 | issue = 8 | pages = 733–739 | date = August 2003 | pmid = 12888794 | doi = 10.1038/ni957 | s2cid = 10305140 }}</ref><ref name="Murphy-2016">{{Cite book | vauthors = Murphy K, Weaver C | title=Janeway's Immunobiology |publisher=Garland Science |year=2016 |isbn=978-0-8153-4505-3 |edition=9th |location=New York, New York |pages=363–364 |language=en}}</ref> 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.<ref name="Itano-2003" /> 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.<ref name="Itano-2003" /><ref name="Gray-2012">{{cite journal | vauthors = Gray EE, Cyster JG | title = Lymph node macrophages | journal = Journal of Innate Immunity | volume = 4 | issue = 5–6 | pages = 424–436 | date = 2012 | pmid = 22488251 | pmc = 3574571 | doi = 10.1159/000337007 }}</ref> 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.<ref name="Murphy-2016" />

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|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 (protein)|B7]]) that binds to [[CD28]] on T helper cells to supply the co-stimulatory signal.<ref name="Murphy-2022"/><ref name="Guerriero-2019" /> 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.<ref name="Guerriero-2019" /> For example, [[Interleukin 2|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 [[IL2RA|IL-2RA]] both require continued signal from TCR recognition of MHC-bound antigen.<ref name="Murphy-2022" /><ref>{{Cite journal | vauthors = Abbas AK |date=September 2020 |title=The Surprising Story of IL-2 |journal=The American Journal of Pathology |language=en |volume=190 |issue=9 |pages=1776–1781 |doi=10.1016/j.ajpath.2020.05.007|pmid=32828360 |s2cid=221280663 |doi-access=free }}</ref>

==== Activation ====
Macrophages can achieve different activation phenotypes through interactions with different subsets of T helper cells, such as T<sub>H</sub>1 and T<sub>H</sub>2.<ref name="Mosser-2008"/> Although there is a broad spectrum of macrophage activation phenotypes, there are two major phenotypes that are commonly acknowledged.<ref name="Mosser-2008" /> 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.<ref name="Mosser-2008" />

===== Classical =====
T<sub>H</sub>1 cells play an important role in classical macrophage activation as part of [[Cell-mediated immunity|type 1 immune response]] against intracellular pathogens (such as [[intracellular bacteria]]) that can survive and replicate inside host cells, especially those pathogens that replicate even after being phagocytosed by macrophages.<ref>{{cite journal | vauthors = Annunziato F, Romagnani C, Romagnani S | title = The 3 major types of innate and adaptive cell-mediated effector immunity | journal = The Journal of Allergy and Clinical Immunology | volume = 135 | issue = 3 | pages = 626–635 | date = March 2015 | pmid = 25528359 | doi = 10.1016/j.jaci.2014.11.001 | doi-access = free }}</ref> After the TCR of T<sub>H</sub>1 cells recognize specific antigen peptide-bound MHC class II molecules on macrophages, T<sub>H</sub>1 cells 1) secrete IFN-γ and 2) upregulate the expression of [[CD154|CD40 ligand]] (CD40L), which binds to [[CD40 (protein)|CD40]] on macrophages.<ref name="Cai-2021">{{cite journal | vauthors = Cai H, Zhang Y, Wang J, Gu J | title = Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1 | journal = Frontiers in Immunology | volume = 12 | pages = 690869 | date = 2021-06-23 | pmid = 34248982 | pmc = 8260839 | doi = 10.3389/fimmu.2021.690869 | doi-access = free }}</ref><ref name="Murphy-2022" /> These 2 signals activate the macrophages and enhance their ability to kill intracellular pathogens through increased production of antimicrobial molecules such as [[nitric oxide]] (NO) and [[superoxide]] (O<sup>2-</sup>).<ref name="Arango Duque-2014"/><ref name="Murphy-2022" /> This enhancement of macrophages' antimicrobial ability by T<sub>H</sub>1 cells is known as classical macrophage activation, and the activated macrophages are known as classically activated macrophages, or M1 macrophages. The M1 macrophages in turn upregulate B7 molecules and antigen presentation through MHC class II molecules to provide signals that sustain T cell help.<ref name="Cai-2021" /> The activation of T<sub>H</sub>1 and M1 macrophage is a positive feedback loop, with IFN-γ from T<sub>H</sub>1 cells upregulating CD40 expression on macrophages; the interaction between CD40 on the macrophages and CD40L on T cells activate macrophages to secrete IL-12; and IL-12 promotes more IFN-γ secretion from T<sub>H</sub>1 cells.<ref name="Murphy-2022" /><ref name="Cai-2021" /> The initial contact between macrophage antigen-bound MHC II and TCR serves as the contact point between the two cells where most of the IFN-γ secretion and CD-40L on T cells concentrate to, so only macrophages directly interacting with T<sub>H</sub>1 cells are likely to be activated.<ref name="Murphy-2022" />

In addition to activating M1 macrophages, T<sub>H</sub>1 cells express [[Fas ligand]] (FasL) and [[lymphotoxin beta]] (LT-β) to help kill chronically infected macrophages that can no longer kill pathogens.<ref name="Murphy-2022" /> The killing of chronically infected macrophages release pathogens to the extracellular space that can then be killed by other activated macrophages.<ref name="Murphy-2022" /> T<sub>H</sub>1 cells also help recruit more monocytes, the precursor to macrophages, to the infection site. T<sub>H</sub>1 secretion [[Tumor necrosis factor|TNF-α]] and [[Lymphotoxin alpha|LT-α]] to make blood vessels easier for monocytes to bind to and exit.<ref name="Murphy-2022" /> T<sub>H</sub>1 secretion of [[CCL2]] as a chemoattractant for monocytes. [[Interleukin 3|IL-3]] and [[Granulocyte-macrophage colony-stimulating factor|GM-CSF]] released by T<sub>H</sub>1 cells stimulate more monocyte production in the bone marrow.<ref name="Murphy-2022" />

When intracellular pathogens cannot be eliminated, such as in the case of ''[[Mycobacterium tuberculosis]]'', the pathogen is contained through the formation of [[granuloma]], an aggregation of infected macrophages surrounded by activated T cells.<ref name="Hilhorst-2014">{{cite journal | vauthors = Hilhorst M, Shirai T, Berry G, Goronzy JJ, Weyand CM | title = T cell-macrophage interactions and granuloma formation in vasculitis | journal = Frontiers in Immunology | volume = 5 | pages = 432 | date = 2014 | pmid = 25309534 | pmc = 4162471 | doi = 10.3389/fimmu.2014.00432 | doi-access = free }}</ref> The macrophages bordering the activated lymphocytes often fuse to form multinucleated giant cells that appear to have increased antimicrobial ability due to their proximity to T<sub>H</sub>1 cells, but over time, the cells in the center start to die and form necrotic tissue.<ref name="Murphy-2016" /><ref name="Hilhorst-2014" />

===== Alternative =====
T<sub>H</sub>2 cells play an important role in alternative macrophage activation as part of type 2 immune response against large extracellular pathogens like [[Parasitic worm|helminths]].<ref name="Murphy-2022" /><ref name="Rolot-2018">{{cite journal | vauthors = Rolot M, Dewals BG | title = Macrophage Activation and Functions during Helminth Infection: Recent Advances from the Laboratory Mouse | journal = Journal of Immunology Research | volume = 2018 | pages = 2790627 | date = 2018-07-02 | pmid = 30057915 | pmc = 6051086 | doi = 10.1155/2018/2790627 | doi-access = free }}</ref> T<sub>H</sub>2 cells secrete IL-4 and IL-13, which activate macrophages to become M2 macrophages, also known as alternatively activated macrophages.<ref name="Rolot-2018" /><ref>{{cite journal | vauthors = Gordon S | title = Alternative activation of macrophages | journal = Nature Reviews. Immunology | volume = 3 | issue = 1 | pages = 23–35 | date = January 2003 | pmid = 12511873 | doi = 10.1038/nri978 | s2cid = 23185583 }}</ref> M2 macrophages express [[Arginase|arginase-1]], an enzyme that converts [[arginine]] to [[ornithine]] and [[urea]].<ref name="Rolot-2018" /> Ornithine help increase smooth muscle contraction to expel the worm and also participates in tissue and wound repair. Ornithine can be further metabolized to [[proline]], which is essential for synthesizing [[collagen]].<ref name="Rolot-2018" /> M2 macrophages can also decrease inflammation by producing IL-1 receptor antagonist (IL-1RA) and IL-1 receptors that do not lead to downstream inflammatory signaling (IL-1RII).<ref name="Murphy-2022" /><ref>{{cite journal | vauthors = Peters VA, Joesting JJ, Freund GG | title = IL-1 receptor 2 (IL-1R2) and its role in immune regulation | journal = Brain, Behavior, and Immunity | volume = 32 | pages = 1–8 | date = August 2013 | pmid = 23195532 | pmc = 3610842 | doi = 10.1016/j.bbi.2012.11.006 }}</ref>

==== Interactions with CD8<sup>+</sup> cytotoxic t cells ====
Another part of the adaptive immunity activation involves stimulating CD8<sup>+</sup> via cross presentation of antigens peptides on MHC class I molecules. Studies have shown that proinflammatory macrophages are capable of cross presentation of antigens on MHC class I molecules, but whether macrophage cross-presentation plays a role in naïve or memory CD8<sup>+</sup> T cell activation is still unclear.<ref name="Punt-2018"/><ref>{{cite journal | vauthors = Muntjewerff EM, Meesters LD, van den Bogaart G | title = Antigen Cross-Presentation by Macrophages | journal = Frontiers in Immunology | volume = 11 | pages = 1276 | date = 2020-07-08 | pmid = 32733446 | pmc = 7360722 | doi = 10.3389/fimmu.2020.01276 | doi-access = free }}</ref><ref name="Gray-2012" />

==== Interactions with B cells ====
Macrophages have been shown to secrete cytokines BAFF and APRIL, which are important for plasma cell isotype switching. APRIL and IL-6 secreted by macrophage precursors in the bone marrow help maintain survival of plasma cells homed to the bone marrow.<ref>{{cite journal | vauthors = Xu W, Banchereau J | title = The antigen presenting cells instruct plasma cell differentiation | journal = Frontiers in Immunology | volume = 4 | pages = 504 | date = January 2014 | pmid = 24432021 | pmc = 3880943 | doi = 10.3389/fimmu.2013.00504 | doi-access = free }}</ref>

==== 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>