Editing Macrophage (section)

==== 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>