Editing Macrophage (section)

== Function ==
[[File:Phagocytosis ZP.svg|thumb|right|400px|'''Steps of a macrophage ingesting a pathogen:'''<br>
'''a.''' Ingestion through phagocytosis, a phagosome is formed<br>'''b.''' The fusion of lysosomes with the phagosome creates a [[phagolysosome]]; the pathogen is broken down by enzymes <br>'''c.''' Waste material is expelled or [[Assimilation (biology)|assimilated]] (the latter not pictured)
<br>'''Parts:'''<br>'''1.''' [[Pathogen]]s<br>'''2.''' [[Phagosome]]<br>'''3.''' [[Lysosome]]s<br>'''4.''' Waste material<br>'''5.''' [[Cytoplasm]]<br>'''6.''' [[Cell membrane]]]]

=== Phagocytosis ===
{{Main|Phagocytosis}}
Macrophages are [[Phagocyte#Professional phagocytes|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 expend themselves and are ingested by macrophages.<ref name="Macro17082013">{{cite journal | vauthors = Eming SA, Krieg T, Davidson JM | title = Inflammation in wound repair: molecular and cellular mechanisms | journal = The Journal of Investigative Dermatology | volume = 127 | issue = 3 | pages = 514–25 | date = March 2007 | pmid = 17299434 | doi = 10.1038/sj.jid.5700701 | quote = =Monocytes/macrophages. Unless stimuli for neutrophil recruitment persist at the wound site, the neutrophil infiltration ceases after few days, and expended neutrophils are themselves phagocytosed by macrophages, which are present at the wound side within 2 days after injury. | doi-access = free }}</ref> Macrophages normally present themselves at the wound site within 2 days following the injury.

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.<ref name=Macro17082013/><ref>{{cite journal | vauthors = Monteith AJ, Miller JM, Maxwell CN, Chazin WJ, Skaar EP | title = Neutrophil extracellular traps enhance macrophage killing of bacterial pathogens | language = EN | journal = Science Advances | volume = 7 | issue = 37 | pages = eabj2101 | date = September 2021 | pmid = 34516771 | pmc = 8442908 | doi = 10.1126/sciadv.abj2101 | bibcode = 2021SciA....7.2101M | doi-access = free }}</ref> The first wave of neutrophils acts for approximately 2 days at the site and signals to attract macrophages. These macrophages will then ingest the aged neutrophils.<ref name="Macro17082013" />

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, [[Nervous tissue|neural tissue]], bone, spleen and connective tissue, ingesting foreign materials such as pathogens and recruiting additional macrophages if needed.<ref>{{Cite journal| vauthors = Verma N, Saraf S |title=A Role of Macrophages: An Overview|date=2017-11-15|url=http://jddtonline.info/index.php/jddt/article/view/1521|journal=Journal of Drug Delivery and Therapeutics|language=en|volume=7|issue=6|pages=91–103|doi=10.22270/jddt.v7i6.1521|issn=2250-1177|doi-access=free}}</ref> The phagocytosis and clearance of apoptotic remains is called [[efferocytosis]] and is also carried out by other cell types, not all of which are professional phagocytes.

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 Salmonella|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.<ref>{{cite journal| vauthors = YashRoy RC |date=2000|title=Hijacking of Macrophages by Salmonella (310r) Through 'Types III' Secretion Like Exocytotic Signalling : A Mechanism for Infection of Chicken Ileum|url=https://www.researchgate.net/publication/230823526|journal=Indian Journal of Poultry Science|volume=35|issue=3|pages=276–281}}</ref> Macrophages are capable of engulfing and digesting many bacteria during their life. They can die eventually due to factors including pathogenic cytotoxicity, oxidative stress, and phagocytosis-induced apoptosis.<ref>{{Cite journal |last=Kirschnek |first=Susanne |last2=Ying |first2=Songmin |last3=Fischer |first3=Silke F. |last4=Häcker |first4=Hans |last5=Villunger |first5=Andreas |last6=Hochrein |first6=Hubertus |last7=Häcker |first7=Georg |date=2005-01-15 |title=Phagocytosis-Induced Apoptosis in Macrophages Is Mediated by Up-Regulation and Activation of the Bcl-2 Homology Domain 3-Only Protein Bim1 |url=https://journals.aai.org/jimmunol/article/174/2/671/72667/Phagocytosis-Induced-Apoptosis-in-Macrophages-Is? |journal=The Journal of Immunology |volume=174 |issue=2 |pages=671–679 |doi=10.4049/jimmunol.174.2.671 |issn=0022-1767}}</ref> Phagocytosis-induced apoptosis results from the powerful apoptotic stimulus of consuming bacteria and is observed in (at least) macrophages and neutrophils.

=== Role in innate immune response ===
When a pathogen invades, tissue resident macrophages are among the first cells to respond.<ref name="Arango Duque-2014">{{cite journal | vauthors = Arango Duque G, Descoteaux A | title = Macrophage cytokines: involvement in immunity and infectious diseases | journal = Frontiers in Immunology | volume = 5 | pages = 491 | date = 2014-10-07 | pmid = 25339958 | pmc = 4188125 | doi = 10.3389/fimmu.2014.00491 | doi-access = free }}</ref> 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.<ref name="Punt-2018">{{Cite book | vauthors = Punt J, Stranford S, Jones P, Owen J |title=Kuby Immunology  |publisher=W. H. Freeman |date=May 25, 2018 |isbn=978-1-4641-8978-4 |edition=8th |location=New York, New York |pages= |language=en}}</ref>

==== Phagocytosis of pathogens ====
[[File:Gram stain of a macrophage with ingested S epidermidis bacteria.jpg|thumb|[[Gram stain]] of a macrophage with ingested ''[[S. epidermidis]]'' bacteria, seen as purple granules within its [[cytoplasm]].]]
Macrophages can internalize antigens through receptor-mediated phagocytosis.<ref name="Fu-2021">{{cite journal | vauthors = Fu YL, Harrison RE | title = Microbial Phagocytic Receptors and Their Potential Involvement in Cytokine Induction in Macrophages | journal = Frontiers in Immunology | volume = 12 | pages = 662063 | date = 2021-04-29 | pmid = 33995386 | pmc = 8117099 | doi = 10.3389/fimmu.2021.662063 | doi-access = free }}</ref> Macrophages have a wide variety of [[pattern recognition receptor]]s (PRRs) that can recognize [[Pathogen-associated molecular pattern|microbe-associated molecular patterns]] (MAMPs) from pathogens. Many PRRs, such as [[toll-like receptor]]s (TLRs), [[Scavenger receptor (immunology)|scavenger receptors]] (SRs), C-type lectin receptors, among others, recognize pathogens for phagocytosis.<ref name="Fu-2021" /> Macrophages can also recognize pathogens for phagocytosis indirectly through [[opsonin]]s, which are molecules that attach to pathogens and mark them for phagocytosis.<ref name="Hirayama-2017">{{cite journal | vauthors = Hirayama D, Iida T, Nakase H | title = The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis | journal = International Journal of Molecular Sciences | volume = 19 | issue = 1 | pages = 92 | date = December 2017 | pmid = 29286292 | pmc = 5796042 | doi = 10.3390/ijms19010092 | doi-access = free }}</ref> Opsonins can cause a stronger adhesion between the macrophage and pathogen during phagocytosis, hence opsonins tend to enhance macrophages’ phagocytic activity.<ref>{{cite journal | vauthors = Uribe-Querol E, Rosales C | title = Phagocytosis: Our Current Understanding of a Universal Biological Process | journal = Frontiers in Immunology | volume = 11 | pages = 1066 | date = 2020-06-02 | pmid = 32582172 | pmc = 7280488 | doi = 10.3389/fimmu.2020.01066 | doi-access = free }}</ref> Both [[Complement system|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 region|fragment crystallizable (Fc) region]] of antigen-bound [[immunoglobulin G]] (IgG) antibodies.<ref name="Hirayama-2017" /><ref>{{cite journal | vauthors = Law SK | title = C3 receptors on macrophages | journal = Journal of Cell Science. Supplement | volume = 9 | issue = Supplement_9 | pages = 67–97 | date = 1988-01-01 | pmid = 2978518 | doi = 10.1242/jcs.1988.Supplement_9.4 | s2cid = 29387085 }}</ref> 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.<ref name="Punt-2018"/><ref>{{cite journal | vauthors = Forman HJ, Torres M | title = Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling | journal = American Journal of Respiratory and Critical Care Medicine | volume = 166 | issue = 12 Pt 2 | pages = S4–S8 | date = December 2002 | pmid = 12471082 | doi = 10.1164/rccm.2206007 | s2cid = 22246117 }}</ref>

==== Chemical 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.<ref name="Fu-2021" /> 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 [[Interleukin 1 beta|IL-1β]], [[Interleukin 6|IL-6]], [[Tumor necrosis factor|TNF-α]], [[Interleukin-12 subunit beta|IL-12B]], and [[Interferon type I|type I interferons]] such as IFN-α and IFN-β.<ref>{{cite journal | vauthors = Liu T, Zhang L, Joo D, Sun SC | title = NF-κB signaling in inflammation | journal = Signal Transduction and Targeted Therapy | volume = 2 | issue = 1 | pages = 17023– | date = 2017-07-14 | pmid = 29158945 | pmc = 5661633 | doi = 10.1038/sigtrans.2017.23 }}</ref> Systemically, IL-1β, IL-6, and TNF-α induce fever and initiate the acute phase response in which the liver secretes [[Acute-phase protein|acute phase proteins]].<ref name="Arango Duque-2014" /><ref name="Punt-2018"/><ref name="Murphy-2022">{{Cite book | vauthors = Murphy K, Weaver C, Berg L |title=Janeway's Immunobiology  |publisher=W. W. Norton & Company |year=2022 |isbn=978-0-393-88487-6 |edition=10th |location=New York, New York |language=en}}</ref> 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]].<ref name="Arango Duque-2014" /><ref name="Punt-2018"/> Additionally, activated macrophages have been found to have delayed synthesis of [[prostaglandin]]s (PGs) which are important mediators of inflammation and pain. Among the PGs, anti-inflammatory [[Prostaglandin E2|PGE2]] and pro-inflammatory [[Prostaglandin D2|PGD2]] increase the most after activation, with PGE2 increasing expression of [[Interleukin 10|IL-10]] and inhibiting production of TNFs via the [[Cyclooxygenase-2|COX-2]] pathway.<ref>{{cite journal | vauthors = Tang T, Scambler ET, Smallie T, Cunliffe HE, et al. | title = Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E2, dual specificity phosphatase 1 and tristetraprolin | journal = Scientific Reports | volume = 7 | issue = 4350 | date = 2017-07-28 | page = 4350 | pmid = 28659609 | pmc = 5489520 | doi = 10.1038/s41598-017-04100-1 }}</ref><ref>{{cite journal |author5-link=Nada Abumrad | vauthors = Hu X, Cifarelli V, Sun S, Kuda O, Abumrad NA, Su X | title = Major role of adipocyte prostaglandin E2 in lipolysis-induced macrophage recruitment | journal = Journal of Lipid Research | volume = 57 | issue = 4 | pages = 663–73 | date = 2016-02-24 | pmid = 26912395 | pmc = 4808775 | doi = 10.1194/jlr.m066530 | doi-access = free }}</ref>

[[Neutrophil]]s are among the first immune cells recruited by macrophages to exit the blood via extravasation and arrive at the infection site.<ref name="Murphy-2022"/> Macrophages secrete many [[chemokine]]s such as [[CXCL1]], [[CXCL2]], and [[Interleukin 8|CXCL8 (IL-8)]] that attract neutrophils to the site of infection.<ref name="Arango Duque-2014" /><ref name="Murphy-2022"/> 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.<ref>{{cite journal | vauthors = Eming SA, Krieg T, Davidson JM | title = Inflammation in wound repair: molecular and cellular mechanisms | journal = The Journal of Investigative Dermatology | volume = 127 | issue = 3 | pages = 514–525 | date = March 2007 | pmid = 17299434 | doi = 10.1038/sj.jid.5700701 | doi-access = free }}</ref>

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]], [[Interleukin 8|CXCL8]], [[CXCL9]], [[CXCL10]], and [[CXCL11]].<ref name="Arango Duque-2014" /><ref name="Murphy-2022"/> Along with dendritic cells, macrophages help activate [[Natural killer cell|natural killer (NK) cells]] through secretion of [[Interferon type I|type I interferons]] (IFN-α and IFN-β) and [[Interleukin 12|IL-12]]. IL-12 acts with [[Interleukin 18|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.<ref name="Murphy-2022"/><ref>{{cite journal | vauthors = Mezouar S, Mege JL | title = Changing the paradigm of IFN-γ at the interface between innate and adaptive immunity: Macrophage-derived IFN-γ | journal = Journal of Leukocyte Biology | volume = 108 | issue = 1 | pages = 419–426 | date = July 2020 | pmid = 32531848 | doi = 10.1002/JLB.4MIR0420-619RR | s2cid = 219622032 }}</ref> IFN-γ enhances the innate immune response by inducing a more aggressive phenotype in macrophages, allowing macrophages to more efficiently kill pathogens.<ref name="Murphy-2022"/>

Some of the T cell chemoattractants secreted by macrophages include [[CCL5]], [[CXCL9]], [[CXCL10]], and [[CXCL11]].<ref name="Arango Duque-2014" />

=== 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>

=== Role in muscle regeneration ===
The first step to understanding the importance of macrophages in muscle repair, growth, and regeneration is that there are two "waves" of macrophages with the onset of damageable muscle use– subpopulations that do and do not directly have an influence on repairing muscle. The initial wave is a phagocytic population that comes along during periods of increased muscle use that are sufficient to cause muscle membrane lysis and membrane inflammation, which can enter and degrade the contents of injured muscle fibers.<ref>{{cite journal | vauthors = Krippendorf BB, Riley DA | title = Distinguishing unloading- versus reloading-induced changes in rat soleus muscle | journal = Muscle & Nerve | volume = 16 | issue = 1 | pages = 99–108 | date = January 1993 | pmid = 8423838 | doi = 10.1002/mus.880160116 | s2cid = 23012375 }}</ref><ref name="St Pierre BA, JG Tidball 1994 290–297">{{cite journal | vauthors = St Pierre BA, Tidball JG | title = Differential response of macrophage subpopulations to soleus muscle reloading after rat hindlimb suspension | journal = Journal of Applied Physiology | volume = 77 | issue = 1 | pages = 290–297 | date = July 1994 | pmid = 7961247 | doi = 10.1152/jappl.1994.77.1.290 }}</ref><ref>{{cite journal | vauthors = Tidball JG, Berchenko E, Frenette J | title = Macrophage invasion does not contribute to muscle membrane injury during inflammation | journal = Journal of Leukocyte Biology | volume = 65 | issue = 4 | pages = 492–498 | date = April 1999 | pmid = 10204578 | doi = 10.1002/jlb.65.4.492 | s2cid = 23315528 | doi-access = free }}</ref> These early-invading, phagocytic macrophages reach their highest concentration about 24 hours following the onset of some form of muscle cell injury or reloading.<ref name="Schiaffino S, Partridge T 2008 380">{{cite book|title=Skeletal Muscle Repair and Regeneration|vauthors=Schiaffino S, Partridge T|year=2008|series=Advances in Muscle Research|volume=3}}</ref> Their concentration rapidly declines after 48 hours.<ref name="St Pierre BA, JG Tidball 1994 290–297"/> The second group is the non-phagocytic types that are distributed near regenerative fibers. These peak between two and four days and remain elevated for several days while muscle tissue is rebuilding.<ref name="St Pierre BA, JG Tidball 1994 290–297"/> The first subpopulation has no direct benefit to repairing muscle, while the second non-phagocytic group does.

It is thought that macrophages release soluble substances that influence the proliferation, differentiation, growth, repair, and regeneration of muscle, but at this time the factor that is produced to mediate these effects is unknown.<ref name="Schiaffino S, Partridge T 2008 380"/> It is known that macrophages' involvement in promoting tissue repair is not muscle specific; they accumulate in numerous tissues during the healing process phase following injury.<ref name="pmid19079608">{{cite journal | vauthors = Bréchot N, Gomez E, Bignon M, Khallou-Laschet J, Dussiot M, Cazes A, Alanio-Bréchot C, Durand M, Philippe J, Silvestre JS, Van Rooijen N, Corvol P, Nicoletti A, Chazaud B, Germain S | title = Modulation of macrophage activation state protects tissue from necrosis during critical limb ischemia in thrombospondin-1-deficient mice | journal = PLOS ONE | volume = 3 | issue = 12 | pages = e3950 | year = 2008 | pmid = 19079608 | pmc = 2597179 | doi = 10.1371/journal.pone.0003950 | doi-access = free | bibcode = 2008PLoSO...3.3950B }}</ref>

=== Role in wound healing ===
Macrophages are essential for [[wound healing]].<ref name="Scholar and Stadelmann">de la Torre J., Sholar A. (2006). [http://www.emedicine.com/plastic/topic477.htm Wound healing: Chronic wounds]. Emedicine.com. Accessed 20 January 2008.</ref> They replace [[polymorphonuclear neutrophil]]s as the predominant cells in the wound by day two after injury.<ref name="Expert Reviews">{{cite journal | journal = Expert Reviews in Molecular Medicine | volume = 5 | date = 21 March 2003 | publisher = Cambridge University Press | url = http://www-ermm.cbcu.cam.ac.uk/03005829a.pdf | title = The phases of cutaneous wound healing | archive-url = https://web.archive.org/web/20081217120738/http://www-ermm.cbcu.cam.ac.uk/03005829a.pdf| archive-date=17 December 2008}}</ref> Attracted to the wound site by growth factors released by platelets and other cells, [[monocyte]]s from the bloodstream enter the area through blood vessel walls.<ref name="Lorenz">{{cite book | vauthors = Lorenz HP, Longaker MT | chapter = Wounds: biology, pathology, and management. | veditors = Li M, Norton JA, Bollinger RR, Chang AE, Lowry SF, Mulvihill SJ, Pass HI, Thompson RW | title = Essential practice of surgery | date = 2003 | pages = 77–88 | publisher = Springer | location = New York, NY | isbn = 978-0-387-22744-3 | chapter-url = http://recon.stanford.edu/Articles/LorenzWH.pdf | archive-url = https://web.archive.org/web/20051031002654/http://recon.stanford.edu/Articles/LorenzWH.pdf| archive-date=31 October 2005}}</ref> Numbers of monocytes in the wound peak one to one and a half days after the injury occurs. Once they are in the wound site, monocytes mature into macrophages. The [[spleen]] contains half the body's monocytes in reserve ready to be deployed to injured tissue.<ref name="Swirski">{{cite journal | vauthors = Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ | title = Identification of splenic reservoir monocytes and their deployment to inflammatory sites | journal = Science | volume = 325 | issue = 5940 | pages = 612–616 | date = July 2009 | pmid = 19644120 | pmc = 2803111 | doi = 10.1126/science.1175202 | bibcode = 2009Sci...325..612S }}</ref><ref name="Jia">{{cite journal | vauthors = Jia T, Pamer EG | title = Immunology. Dispensable but not irrelevant | journal = Science | volume = 325 | issue = 5940 | pages = 549–550 | date = July 2009 | pmid = 19644100 | pmc = 2917045 | doi = 10.1126/science.1178329 | bibcode = 2009Sci...325..549J }}</ref>

The macrophage's main role is to phagocytize bacteria and damaged tissue,<ref name="Scholar and Stadelmann"/> and they also [[Debridement|debride]] damaged tissue by releasing proteases.<ref name="Deodhar and Rana">{{cite journal | vauthors = Deodhar AK, Rana RE | title = Surgical physiology of wound healing: a review | journal = Journal of Postgraduate Medicine | volume = 43 | issue = 2 | pages = 52–56 | year = 1997 | pmid = 10740722 | url = http://www.jpgmonline.com/article.asp?issn=0022-3859;year=1997;volume=43;issue=2;spage=52;epage=6;aulast=Deodhar }}</ref> Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wound days. These factors attract cells involved in the proliferation stage of healing to the area.<ref name="Rosenberg and de la Torre, 2006">Rosenberg L., de la Torre J. (2006). [http://www.emedicine.com/plastic/topic457.htm Wound Healing, Growth Factors]. Emedicine.com. Accessed 20 January 2008.</ref> Macrophages may also restrain the contraction phase.<ref name="springerlink.com">{{cite journal | vauthors = Newton PM, Watson JA, Wolowacz RG, Wood EJ | title = Macrophages restrain contraction of an in vitro wound healing model | journal = Inflammation | volume = 28 | issue = 4 | pages = 207–214 | date = August 2004 | pmid = 15673162 | doi = 10.1023/B:IFLA.0000049045.41784.59 | s2cid = 9612298 }}</ref> Macrophages are stimulated by the low [[oxygen]] content of their surroundings to produce factors that induce and speed [[angiogenesis]]<ref name="Greenhalgh">{{cite journal | vauthors = Greenhalgh DG | title = The role of apoptosis in wound healing | journal = The International Journal of Biochemistry & Cell Biology | volume = 30 | issue = 9 | pages = 1019–1030 | date = September 1998 | pmid = 9785465 | doi = 10.1016/S1357-2725(98)00058-2 }}</ref> and they also stimulate cells that re-epithelialize the wound, create granulation tissue, and lay down a new [[extracellular matrix]].<ref name="Stashak">{{cite journal| vauthors = Stashak TS, Farstvedt E, Othic A |date=June 2004|title=Update on wound dressings: Indications and best use|journal=Clinical Techniques in Equine Practice|volume=3|issue=2|pages=148–163|doi=10.1053/j.ctep.2004.08.006 }}</ref>{{better source needed|date=August 2017}} By secreting these factors, macrophages contribute to pushing the wound healing process into the next phase.

=== Role in limb regeneration ===
Scientists have elucidated that as well as eating up material debris, macrophages are involved in the typical [[limb regeneration]] in the salamander.<ref name="macr20130523">{{cite web|url=https://www.theverge.com/2013/5/23/4358418/salamander-macrophages-could-aid-limb-regeneration|title=Scientists identify cell that could hold the secret to limb regeneration| vauthors = Souppouris A  |date=2013-05-23|publisher=the verge.com|quote=Researchers have identified a cell that aids limb regrowth in Salamanders. Macrophages are a type of repairing cell that devour dead cells and pathogens, and trigger other immune cells to respond to pathogens.}}</ref><ref name="Macrpnas2013">{{cite journal | vauthors = Godwin JW, Pinto AR, Rosenthal NA | title = Macrophages are required for adult salamander limb regeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 23 | pages = 9415–9420 | date = June 2013 | pmid = 23690624 | pmc = 3677454 | doi = 10.1073/pnas.1300290110 | doi-access = free | bibcode = 2013PNAS..110.9415G }}</ref> They found that removing the macrophages from a [[salamander]] resulted in failure of limb regeneration and a scarring response.<ref name=macr20130523/><ref name=Macrpnas2013/>

=== Role in iron homeostasis ===
{{Main|Human iron metabolism}}

As described above, macrophages play a key role in removing dying or dead cells and cellular debris. [[Red blood cell|Erythrocytes]] have a lifespan on average of 120 days and so are constantly being destroyed by macrophages in the spleen and liver. Macrophages will also engulf [[macromolecule]]s, and so play a key role in the [[pharmacokinetics]] of [[parenteral iron]]s.{{citation needed|date=November 2021}}

The iron that is released from the haemoglobin is either stored internally in [[ferritin]] or is released into the circulation via [[ferroportin]]. In cases where systemic iron levels are raised, or where inflammation is present, raised levels of [[hepcidin]] act on macrophage ferroportin channels, leading to iron remaining within the macrophages.<ref name="melkaya94">{{cite web |title=Iron metabolism and iron disorders revisited in the hepcidin era |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC7012465/ |website=National Library of Medicine |access-date=29 April 2025}}</ref>

=== Role in pigment retainment ===
[[File:Micrograph of a melanophage.jpg|thumb|150px|Melanophage. H&E stain.]]
{{anchor|Melanophage}}Melanophages are a subset of tissue-resident macrophages able to absorb pigment, either native to the organism or exogenous (such as [[tattoo]]s), from extracellular space. In contrast to dendritic juncional [[melanocyte]]s, which [[Melanin|synthesize melanosomes]] and contain various stages of their development, the melanophages only accumulate [[Phagocytosis|phagocytosed]] melanin in lysosome-like phagosomes.<ref>{{cite journal | vauthors = Mishima Y | title = Lysosomes in malanin phagocytosis and synthesis | language = En | journal = Nature | volume = 216 | issue = 5110 | pages = 67 | date = October 1967 | pmid = 6050674 | doi = 10.1038/216067a0 | s2cid = 4285140 | bibcode = 1967Natur.216...67M | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mishima Y | title = Cellular and subcellular differentiation of melanin phagocytosis and synthesis by lysosomal and melanosomal activity | journal = The Journal of Investigative Dermatology | volume = 46 | issue = 1 | pages = 70–75 | date = January 1966 | pmid = 5905254 | doi = 10.1038/jid.1966.11 | doi-access = free }}</ref> This occurs repeatedly as the pigment from dead dermal macrophages is phagocytosed by their successors, preserving the tattoo in the same place.<ref>{{cite journal | vauthors = Baranska A, Shawket A, Jouve M, Baratin M, Malosse C, Voluzan O, Vu Manh TP, Fiore F, Bajénoff M, Benaroch P, Dalod M, Malissen M, Henri S, Malissen B | title = Unveiling skin macrophage dynamics explains both tattoo persistence and strenuous removal | journal = The Journal of Experimental Medicine | volume = 215 | issue = 4 | pages = 1115–1133 | date = April 2018 | pmid = 29511065 | pmc = 5881467 | doi = 10.1084/jem.20171608 }}</ref>

=== Role in tissue homeostasis ===
Every tissue harbors its own specialized population of resident macrophages, which entertain reciprocal interconnections with the stroma and functional tissue.<ref>{{cite journal | vauthors = Okabe Y, Medzhitov R | title = Tissue-specific signals control reversible program of localization and functional polarization of macrophages | journal = Cell | volume = 157 | issue = 4 | pages = 832–844 | date = May 2014 | pmid = 24792964 | pmc = 4137874 | doi = 10.1016/j.cell.2014.04.016 }}</ref><ref>{{cite journal | vauthors = Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK | title = Environment drives selection and function of enhancers controlling tissue-specific macrophage identities | journal = Cell | volume = 159 | issue = 6 | pages = 1327–1340 | date = December 2014 | pmid = 25480297 | pmc = 4364385 | doi = 10.1016/j.cell.2014.11.023 }}</ref> These resident macrophages are sessile (non-migratory), provide essential growth factors to support the physiological function of the tissue (e.g. macrophage-neuronal crosstalk in the guts),<ref>{{cite journal | vauthors = Muller PA, Koscsó B, Rajani GM, Stevanovic K, Berres ML, Hashimoto D, Mortha A, Leboeuf M, Li XM, Mucida D, Stanley ER, Dahan S, Margolis KG, Gershon MD, Merad M, Bogunovic M | title = Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility | journal = Cell | volume = 158 | issue = 2 | pages = 300–313 | date = July 2014 | pmid = 25036630 | pmc = 4149228 | doi = 10.1016/j.cell.2014.04.050 }}</ref> and can actively protect the tissue from inflammatory damage.<ref>{{cite journal | vauthors = Uderhardt S, Martins AJ, Tsang JS, Lämmermann T, Germain RN | title = Resident Macrophages Cloak Tissue Microlesions to Prevent Neutrophil-Driven Inflammatory Damage | journal = Cell | volume = 177 | issue = 3 | pages = 541–555.e17 | date = April 2019 | pmid = 30955887 | pmc = 6474841 | doi = 10.1016/j.cell.2019.02.028 }}</ref>

=== Nerve-associated macrophages ===
Nerve-associated macrophages or NAMs are those tissue-resident macrophages that are associated with nerves. Some of them are known to have an elongated morphology of up to 200μm <ref>{{cite journal | vauthors = Kolter J, Kierdorf K, Henneke P | title = Origin and Differentiation of Nerve-Associated Macrophages | journal = Journal of Immunology | volume = 204 | issue = 2 | pages = 271–279 | date = January 2020 | pmid = 31907269 | doi = 10.4049/jimmunol.1901077 | s2cid = 210043405 | doi-access = free }}</ref>