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= Macrophage Polarization =
'''Macrophage polarization''' is a process when [[macrophage]] expresses different functional programs in response to microenvironmental signals.<ref>Mantovani, Alberto, et al. "Macrophage polarization: tumour-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes." Trends in immunology 23.11 (2002): 549-555.</ref> There are lots of functional states of macrophage polarization and they can be fully polarized and acquire specific phenotype like M1 (classically activated macrophages) or M2 (alternatively activated macrophages). <ref>Hamilton, T. A. (2014). "Myeloid Colony Stimulating Factors as Regulators of Macrophage Polarization." Frontiers in Immunology</ref> These specific phenotypes depend on the tissue and specific microenvironment where macrophages are. <ref>Lawrence, Toby, and Gioacchino Natoli. "Transcriptional regulation of macrophage polarization: enabling diversity with identity." Nature reviews immunology 11.11 (2011): 750-761.</ref> On one hand macrophage polarization is very important for host defense against [[pathogen]], but on the other hand it is essential for maintenance of [[homeostasis]]. <ref>Hamilton, Thomas A., et al. "Myeloid colony-stimulating factors as regulators of macrophage polarization." Frontiers in immunology 5 (2014). </ref> Prolonged M1 type of macrophages is harmful for the organism and that is why tissue repair and restoration is necessary. M2 macrophages are responsible for that although they are connected with chronic [[List of infectious diseases|infectious diseases]]. <ref>Benoit, Marie, Benoît Desnues, and Jean-Louis Mege. "Macrophage polarization in bacterial infections." The Journal of Immunology 181.6 (2008): 3733-3739. </ref>
== M1 macrophages ==
Classically activated macrophages was named by Mackaness in the 1960s <ref>Mackaness GB: Cellular resistance to infection. J Exp Med 1962,116:381-406. </ref>. They express transcription factors like interferon-regulatory factor ([[IRF5]]), nuclear factor of kappa light polypeptide gene enhancer ([[NF-kB]]), activator protein 1 ([[AP-1]]) and [[STAT1]]. <ref> Krausgruber, Thomas, et al. "IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses." Nature immunology 12.3 (2011): 231-238.</ref>Typical are pro – inflammatory molecules (e.g. [[IFN-γ]], [[IL-12]], [[IL-23]], [[TNF]], [[Interleukin 6|IL-6]], [[IL-1]], specific chemokines and [[Major histocompatibility complex|antigen presentation molecules]]).
M1 macrophages are irreplaceable during acute infectious diseases and provide host protection against [[intracellular bacteria]] or [[virus|viruses]] by production of nitric oxide ([[NO]]) or reactive oxygen intermediates ([[ROI]]). <ref>Sica, Antonio, et al. "Macrophage polarization in tumour progression."Seminars in cancer biology. Vol. 18. No. 5. Academic Press, 2008. </ref> <ref>Martinez, Fernando O., and Siamon Gordon. "The M1 and M2 paradigm of macrophage activation: time for reassessment." F1000prime reports 6 (2014). </ref> IFN-γ produced by Th1 lymphocytes is the most important cytokine which is responsible for classical macrophage activation. [[Natural killer cell|Natural killer (NK) cells]] and macrophages themselves produce IFN-γ as well. This [[cytokine]] regulates gene expression programs of macrophages like [[Cytokine receptor|cytokine receptors]], cell activation markers or [[Cell adhesion molecule|cell adhesion molecules]]. For classical macrophage activation is necessary also [[lipopolysaccharide]] (LPS) – typical for [[gram negative bacteria]] – which is mainly recognised by [[TLR4]], or [[lipoteichoic acid]] (LTA) – typical for [[gram positive bacteria]]. Granulocyte – macrophage colony stimulation factor ([[GM-CSF]]) stimulates M1 too. <ref>Martinez, Fernando O., and Siamon Gordon. "The M1 and M2 paradigm of macrophage activation: time for reassessment." F1000prime reports 6 (2014). </ref>
== M2 macrophages ==
Alternatively activated macrophages cover a continuum of functional states which are divided into groups – M2a, M2b and M2c macrophages. <ref>Mantovani, Alberto, et al. "The chemokine system in diverse forms of macrophage activation and polarization." Trends in immunology 25.12 (2004): 677-686. </ref>There are different stimuli for each type – interleukin-4 ([[IL-4]]), [[IL-13]] (M2a), [[immune complex]] + Toll-like receptor ([[TLR]]) or [[Interleukin-1 receptor|IL-1 receptor]] ligands (M2b), [[IL-10]] and [[Glucocorticoid|glucocorticoids]] (M2c).
M2a macrophages are connected with Th2 immune response. Th2 cells, eosinophils, basophils and macrophages themselves produce IL-4. They are important for encapsulation of parasites but they are also responsible for the [[Type II hypersensitivity|type II hypersensitivity]]. For M2b is common increased IL-10 production but IL-12 production is turned off. Antigen presentation is upregulated ([[MHC II]], [[CD86]]). M2c macrophages are important for secretion of IL-10, [[TGF-β]]. They also contribute on production of [[extracellular matrix]] components and tissue remodeling. Glucocorticoids influence their adherence, dissemination, [[apoptosis]] and [[phagocytosis]] of macrophage. <ref>Martinez, Fernando O., and Siamon Gordon. "The M1 and M2 paradigm of macrophage activation: time for reassessment." F1000prime reports 6 (2014). </ref>
== Tumour associated macrophages ==
Tumour associated macrophages (TAM) are typical for their protumoural functions like promotion of cancer cell motility, [[metastasis]] formation and [[angiogenesis]] <ref> Lewis, Claire E., and Jeffrey W. Pollard. "Distinct role of macrophages in different tumor microenvironments." Cancer research 66.2 (2006): 605-612. </ref> and their formation is dependent on microenvironmetal factors which are present in developing tumour. <ref>Sica, Antonio, et al. "Macrophage polarization in tumour progression."Seminars in cancer biology. Vol. 18. No. 5. Academic Press, 2008. </ref>
TAMs produce immunosuppressive cytokines like [[IL-10]], [[TGFβ]] and [[PGE2]] very small amount of NO or ROI and low levels of inflammatory cytokines ([[IL-12]], [[IL-1β]], [[TNFα]], [[IL-6]]). <ref> Sica, Antonio, et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol. 2000 Jan 15;164(2):762-7. </ref> Ability of TAMs to present tumour-associated antigens is decreased as well as stimulation of the anti-tumour functions of T and NK cells. Also TAMs are not able to lyse tumour cells. <ref>Sica, Antonio, et al. "Macrophage polarization in tumour progression."Seminars in cancer biology. Vol. 18. No. 5. Academic Press, 2008. </ref>
Targeting of TAM may be a novel therapeutic strategy against cancer.
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