Biology:Macrophage polarization

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Macrophage polarization is a process by which macrophages adopt different functional programs in response to the signals from their microenvironment. This ability is connected to their multiple roles in the organism: they are powerful effector cells of the innate immune system, but also important in removal of cellular debris, embryonic development and tissue repair.[1] By simplified classification, macrophage phenotype has been divided into 2 groups: M1 (classically activated macrophages) and M2 (alternatively activated macrophages). This broad classification was based on in vitro studies, in which cultured macrophages were treated with molecules that stimulated their phenotype switching to a particular state.[2] In addition to chemical stimulation, it has been shown that the stiffness of the underlying substrate a macrophage is grown on can direct polarization state, functional roles and migration mode.[3] A continuum of M1-M2 polarization may arise even in the absence of polarizing cytokines and differences in substrate stiffness.[4] M1 macrophages were described as the pro-inflammatory type, important in direct host-defense against pathogens, such as phagocytosis and secretion of pro-inflammatory cytokines and microbicidal molecules. M2 macrophages were described to have quite the opposite function: regulation of the resolution phase of inflammation and the repair of damaged tissues. Later, more extensive in vitro and ex vivo studies have shown that macrophage phenotypes are much more diverse, overlapping with each other in terms of gene expression and function, revealing that these many hybrid states form a continuum of activation states which depend on the microenvironment.[5][6][7][8] Moreover, in vivo, there is a high diversity in gene expression profile between different populations of tissue macrophages.[9] Macrophage activation spectrum is thus considered to be wider, involving complex regulatory pathway to response to plethora of different signals from the environment.[10][11] The diversity of macrophage phenotypes still remain to be fully characterized in vivo.

The imbalance of the macrophage types is related to a number of immunity-related diseases.[12][13] For example, it has been shown that increased M1/M2 ratio correlates with development of inflammatory bowel disease,[14][15] as well as obesity in mice.[16][17][18] On the other side, in vitro experiments implicated M2 macrophages as the primary mediators of tissue fibrosis.[13] Several studies have associated the fibrotic profile of M2 macrophages with the pathogenesis of systemic sclerosis.[12][19]

Types

M1

Classically activated macrophages (M1) were named by G. B. Mackaness in the 1960s.[20] M1-activation in vitro is evoked by treatment with TLR ligands such as bacterial lipopolysaccharide (LPS) - typical for Gram-negative bacteria and lipoteichoic acid (LTA) - typical for Gram-positive bacteria, granulocyte-macrophage colony-stimulating factor (GM-CSF) or combination of LPS and interferon-gamma (IFN-γ).[2][21][22] Similarly in vivo, classically activated macrophages arise in response to IFN-γ produced by Th1 lymphocytes or by natural killer cells (NK), and tumor-necrosis factor (TNF), produced by antigen-presenting cells (APCs).[22]

M1-activated macrophages express transcription factors such as interferon regulatory factor (IRF5), nuclear factor of kappa light polypeptide gene enhancer (NF-κB), activator protein (AP-1) and STAT1. This leads to enhanced microbicidal capacity and secretion of high levels of pro-inflammatory cytokines: e.g. IFN-γ, IL-1, IL-6, IL-12, IL-23 and TNFα. Moreover, to increase their pathogen-killing ability, they produce increased amounts of chemicals called reactive oxygen species (ROS) and nitrogen radicals (caused by upregulation of inducible NO synthase iNOS).[5][23] Thanks to their ability to fight pathogens, M1 macrophages are present during acute infectious diseases. A number of studies have shown that bacterial infection induces polarization of macrophages toward the M1 phenotype, resulting in phagocytosis and intracellular killing of bacteria in vitro and in vivo. For instance, Listeria monocytogenes, a Gram-positive bacteria causing listeriosis is shown to induce an M1 polarization,[24][25] as well as Salmonella Typhi (the agent of typhoid fever) and Salmonella Typhimurium (causing gastroenteritis), which are shown to induce the M1 polarization of human and murine macrophages.[25] Macrophages are polarized toward the M1 profile during the early phase of Mycobacterium tuberculosis infection,[26] as well as other mycobacterial species such as Mycobacterium ulcerans (causing Buruli ulcer disease) and Mycobacterium avium.[25]

Improper and untimely control of M1 macrophage-mediated inflammatory response can lead to disruption of normal tissue homeostasis and impede vascular repair. An uncontrolled production of pro-inflammatory cytokines during the inflammation can lead to the formation of cytokine storm, thereby contributing to the pathogenesis of severe sepsis.[27] In order to counteract the inflammatory response, macrophages undergo apoptosis or polarize to an M2 phenotype to protect the host from the excessive injury.[23]

M2

Alternatively activated macrophages (M2) were discovered in early 1990s and named according to previously-discovered Th2 cell-mediated anti-inflammatory response.[23] M2 macrophages resolve inflammation, help tissue healing, tolerate self-antigens and certain neoantigens (for example apoptotic cells, symbiont cells, gametes and cells of the embryo in the uterus). M2 macrophages hence govern functions at the interfaces of immunity, tissue development and turnover, metabolism, and endocrine signaling.[28] It is shown in vitro that macrophage treatment with IL-4 and IL-13 leads to inhibition of pro-inflammatory signals production and upregulation of scavenging mannose receptor CD206.[23] Further studies have shown that M2 polarization may be induced through different activation signals leading in fact to different M2 phenotypes having different roles. It has first been suggested that M2 macrophages can be divided in two groups: regulatory and wound-healing macrophages. Regulatory macrophages were described to have anti-inflammatory properties, which are important in resolutive phases of the inflammation, producing the immunosuppressive cytokine IL-10. Differentiation toward the regulatory macrophage phenotype may be triggered by immune complexes, prostaglandins, apoptotic cells and IL-10. On the other side, wound healing macrophages were shown to produce IL-4 and upregulate arginase activity, which is the enzyme enrolled in production of polyamines and collagen, thus regenerating the damaged tissue.[5][6]

Further investigation of M2 subtypes led to even more complex systematization, where the authors describe M2a, M2b, and M2c subtype.[7][12] M2a macrophages are activated by IL-4 and IL-13 which evokes upregulated expression of arginase-1, mannose receptor MRc1 (CD206), antigen presentation by MHC II system, and production of IL-10 and TGF-𝛽, leading to tissue regeneration and internalization of pro-inflammatory molecules to prevent the inflammatory response. The M2b macrophages produce IL-1, IL-6, IL-10, TNF-𝛼 as a response to immune complexes or LPS, leading to activation of Th2 cells and anti-inflammatory activity. M2c macrophages are activated by IL-10, transforming growth factor beta (TGF-𝛽) and glucocorticoids, and produce IL-10 and TGFβ, leading to suppression of inflammatory response. Some authors mention the M2d subtype activation as a response to IL-6 and adenosines, and these macrophages are also referred as tumor-associated macrophages (TAM).[7][12][29]

Although M2 activation state involves heterogeneous macrophage populations, some markers are shared between subtypes, thus the strict macrophage division into subtypes is not possible so far. In mice, CD206 or the mannose receptor marker can be used to differentiate the M2 from M1. Moreover, the in vivo translation of these M2 subdivisions is difficult. Tissues contain complex range of stimuli leading to mixed macrophage populations with a wide spectrum of activation states.[7][30]

Continuum of polarization states

A lot remains to be learned about macrophage polarized activation states and their role in immune response. Since there is not a rigid barrier between described macrophage phenotypes and that known markers are expressed by more than one of these activation states,[5][30] it is impossible so far to classify macrophage subtypes in proper and precise way. Thus their differences are rather considered as a continuum of functional states without clear boundaries. Moreover, it is observed that macrophage states are changing during the time course of the inflammation and disease.[30][31] This plasticity of macrophage phenotype has added to the confusion regarding the existence of individual macrophage sub-types in vivo.[30][32]

Tumour associated macrophages

Tumour-associated macrophages (TAM) are typical for their protumoural functions like promotion of cancer cell motility, metastasis formation and angiogenesis[33] and their formation is dependent on microenvironmetal factors which are present in developing tumour.[34] 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).[35] 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.[34] Targeting of TAM may be a novel therapeutic strategy against cancer, as has been demonstrated through the delivery of agents to either alter the recruitment and distribution of TAMs,[36] deplete existing TAMs,[37] or induce the re-education of TAMs from an M2 to an M1 phenotype.[38][39]

Tissue resident macrophages

Some macrophages are known to be residing in the tissues and help in maintaining the tissue microenvironment. These came to be known as tissue resident macrophages(TRMs). The TRMs in the pancreatic islets are known to be inflammatory in nature and fall under the M1 category.[40]

References

  1. ↑ "Macrophage biology in development, homeostasis and disease". Nature 496 (7446): 445–55. April 2013. doi:10.1038/nature12034. PMID 23619691. Bibcode: 2013Natur.496..445W. 
  2. ↑ 2.0 2.1 "M-1/M-2 macrophages and the Th1/Th2 paradigm". Journal of Immunology 164 (12): 6166–73. June 2000. doi:10.4049/jimmunol.164.12.6166. PMID 10843666. 
  3. ↑ "Material stiffness influences the polarization state, function and migration mode of macrophages". Acta Biomaterialia 89: 47–59. April 2019. doi:10.1016/j.actbio.2019.02.048. PMID 30826478. 
  4. ↑ "Single-cell proteomic and transcriptomic analysis of macrophage heterogeneity using SCoPE2". Genome Biology 22 (1): 50. January 2021. doi:10.1186/s13059-021-02267-5. PMID 33504367. 
  5. ↑ 5.0 5.1 5.2 5.3 "Exploring the full spectrum of macrophage activation". Nature Reviews. Immunology 8 (12): 958–69. December 2008. doi:10.1038/nri2448. PMID 19029990. 
  6. ↑ 6.0 6.1 "Alternatively activated macrophages in helminth infections". Current Opinion in Immunology 19 (4): 448–53. August 2007. doi:10.1016/j.coi.2007.07.002. PMID 17702561. 
  7. ↑ 7.0 7.1 7.2 7.3 "Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms". Mediators of Inflammation 2015: 816460. 2015. doi:10.1155/2015/816460. PMID 26089604. 
  8. ↑ "Transcriptome-based network analysis reveals a spectrum model of human macrophage activation". Immunity 40 (2): 274–88. February 2014. doi:10.1016/j.immuni.2014.01.006. PMID 24530056. 
  9. ↑ "Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages". Nature Immunology 13 (11): 1118–28. November 2012. doi:10.1038/ni.2419. PMID 23023392. 
  10. ↑ "Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment". Cell 159 (6): 1312–26. December 2014. doi:10.1016/j.cell.2014.11.018. PMID 25480296. 
  11. ↑ "New insights into the multidimensional concept of macrophage ontogeny, activation and function". Nature Immunology 17 (1): 34–40. January 2016. doi:10.1038/ni.3324. PMID 26681460. 
  12. ↑ 12.0 12.1 12.2 12.3 "Implications of macrophage polarization in autoimmunity". Immunology 154 (2): 186–195. June 2018. doi:10.1111/imm.12910. PMID 29455468. 
  13. ↑ 13.0 13.1 "The significance of macrophage polarization subtypes for animal models of tissue fibrosis and human fibrotic diseases". Clinical and Translational Medicine 4: 2. 2015. doi:10.1186/s40169-015-0047-4. PMID 25852818. 
  14. ↑ "Monocyte and M1 Macrophage-induced Barrier Defect Contributes to Chronic Intestinal Inflammation in IBD". Inflammatory Bowel Diseases 21 (6): 1297–305. June 2015. doi:10.1097/MIB.0000000000000384. PMID 25901973. 
  15. ↑ "Disequilibrium of M1 and M2 macrophages correlates with the development of experimental inflammatory bowel diseases". Immunological Investigations 43 (7): 638–52. 2014. doi:10.3109/08820139.2014.909456. PMID 24921428. 
  16. ↑ "Obesity induces a phenotypic switch in adipose tissue macrophage polarization". The Journal of Clinical Investigation 117 (1): 175–84. January 2007. doi:10.1172/jci29881. PMID 17200717. 
  17. ↑ "Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype". The Journal of Biological Chemistry 285 (9): 6153–60. February 2010. doi:10.1074/jbc.m109.088708. PMID 20028977. 
  18. ↑ "Accumulation of M1-like macrophages in type 2 diabetic islets is followed by a systemic shift in macrophage polarization". Journal of Leukocyte Biology 95 (1): 149–60. January 2014. doi:10.1189/jlb.0213075. PMID 24009176. 
  19. ↑ "Increased presence of CD206+ macrophage subset in peripheral blood of systemic sclerosis patients.". Annals of the Rheumatic Diseases 74 (Supplement 1): A5–6. 2015. doi:10.1136/annrheumdis-2015-207259.13. 
  20. ↑ "Cellular resistance to infection". The Journal of Experimental Medicine 116 (3): 381–406. September 1962. doi:10.1084/jem.116.3.381. PMID 14467923. 
  21. ↑ "IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses". Nature Immunology 12 (3): 231–8. March 2011. doi:10.1038/ni.1990. PMID 21240265. 
  22. ↑ 22.0 22.1 "The M1 and M2 paradigm of macrophage activation: time for reassessment". F1000Prime Reports 6: 13. 2014. doi:10.12703/P6-13. PMID 24669294. 
  23. ↑ 23.0 23.1 23.2 23.3 "Macrophage polarization in inflammatory diseases". International Journal of Biological Sciences 10 (5): 520–9. 2014. doi:10.7150/ijbs.8879. PMID 24910531. 
  24. ↑ "The role of the activated macrophage in clearing Listeria monocytogenes infection". Frontiers in Bioscience 12 (7): 2683–92. January 2007. doi:10.2741/2264. PMID 17127272. 
  25. ↑ 25.0 25.1 25.2 "Macrophage polarization in bacterial infections". Journal of Immunology 181 (6): 3733–9. September 2008. doi:10.4049/jimmunol.181.6.3733. PMID 18768823. 
  26. ↑ "Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes". Clinical and Experimental Immunology 140 (3): 443–9. June 2005. doi:10.1111/j.1365-2249.2005.02797.x. PMID 15932505. 
  27. ↑ "Macrophages in Tissue Repair, Regeneration, and Fibrosis". Immunity 44 (3): 450–462. March 2016. doi:10.1016/j.immuni.2016.02.015. PMID 26982353. 
  28. ↑ The M2 Macrophage (1 ed.). Springer. 2020. ISBN 978-3-030-50479-3. https://www.springer.com/gp/book/9783030504793. 
  29. ↑ "Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages". Cell Research 20 (6): 701–12. June 2010. doi:10.1038/cr.2010.52. PMID 20386569. 
  30. ↑ 30.0 30.1 30.2 30.3 "Macrophage activation and polarization: nomenclature and experimental guidelines". Immunity 41 (1): 14–20. July 2014. doi:10.1016/j.immuni.2014.06.008. PMID 25035950. 
  31. ↑ "Identification of polarized macrophage subsets in zebrafish". eLife 4: e07288. July 2015. doi:10.7554/eLife.07288. PMID 26154973. 
  32. ↑ "Heterogeneity of macrophage activation in fish". Developmental and Comparative Immunology 35 (12): 1246–55. December 2011. doi:10.1016/j.dci.2011.03.008. PMID 21414343. 
  33. ↑ "Distinct role of macrophages in different tumor microenvironments". Cancer Research 66 (2): 605–12. January 2006. doi:10.1158/0008-5472.CAN-05-4005. PMID 16423985. 
  34. ↑ 34.0 34.1 "Macrophage polarization in tumour progression". Seminars in Cancer Biology 18 (5): 349–55. October 2008. doi:10.1016/j.semcancer.2008.03.004. PMID 18467122. 
  35. ↑ "Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages". Journal of Immunology 164 (2): 762–7. January 2000. doi:10.4049/jimmunol.164.2.762. PMID 10623821. 
  36. ↑ "Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging" (in En). Nature Communications 8: 14293. February 2017. doi:10.1038/ncomms14293. PMID 28176769. Bibcode: 2017NatCo...814293C. 
  37. ↑ "Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach". British Journal of Cancer 95 (3): 272–81. August 2006. doi:10.1038/sj.bjc.6603240. PMID 16832418. 
  38. ↑ "TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy" (in En). Nature Biomedical Engineering 2 (8): 578–588. August 2018. doi:10.1038/s41551-018-0236-8. PMID 31015631. 
  39. ↑ "Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages" (in En). Nature 543 (7645): 428–432. March 2017. doi:10.1038/nature21409. PMID 28273064. Bibcode: 2017Natur.543..428G. 
  40. ↑ "The islet-resident macrophage is in an inflammatory state and senses microbial products in blood" (in En). Journal of Experimental Medicine 214 (8): 2369–2385. 2017. doi:10.1084/jem.20170074. PMID 28630088. 



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