Current Concept and Update of the Macrophage Plasticity Concept: Intracellular Mechanisms of Reprogramming and M3 Macrophage "Switch" Phenotype

Overview

Journal Biomed Res Int

Publisher Wiley

Specialties Biomedical Engineering
Biotechnology
General Medicine

Date 2015 Sep 15

PMID 26366410

Citations 125

Authors

Igor Malyshev

Yuri Malyshev

Affiliations

Soon will be listed here.

Abstract

Macrophages play a key role in immunity. In this review, we consider the traditional notion of macrophage plasticity, data that do not fit into existing concepts, and a hypothesis for existence of a new switch macrophage phenotype. Depending on the microenvironment, macrophages can reprogram their phenotype toward the proinflammatory M1 phenotype or toward the anti-inflammatory M2 phenotype. Macrophage reprogramming involves well-coordinated changes in activities of signalling and posttranslational mechanisms. Macrophage reprogramming is provided by JNK-, PI3K/Akt-, Notch-, JAK/STAT-, TGF-β-, TLR/NF-κB-, and hypoxia-dependent pathways. Posttranscriptional regulation is based on micro-mRNA. We have hypothesized that, in addition to the M1 and M2 phenotypes, an M3 switch phenotype exists. This switch phenotype responds to proinflammatory stimuli with reprogramming towards the anti-inflammatory M2 phenotype or, contrarily, it responds to anti-inflammatory stimuli with reprogramming towards the proinflammatory M1 phenotype. We have found signs of such a switch phenotype in lung diseases. Understanding the mechanisms of macrophage reprogramming will assist in the selection of new therapeutic targets for correction of impaired immunity.

Citing Articles

STAT signaling pathways in immune cells and their associated mechanisms in cancer pathogenesis.

Sohrabi S, Alipour S, Ghahramanipour Z, Masoumi J, Baradaran B Bioimpacts. 2025; 15:30030.

PMID: 39963570 PMC: 11830145. DOI: 10.34172/bi.30030.

Harnessing amino acid pathways to influence myeloid cell function in tumor immunity.

Pan J, Lin Y, Liu X, Zhang X, Liang T, Bai X Mol Med. 2025; 31(1):44.

PMID: 39905317 PMC: 11796060. DOI: 10.1186/s10020-025-01099-4.

Tumor microenvironment noise-induced polarization: the main challenge in macrophages' immunotherapy for cancer.

Sierra J, de Leon U, Padilla-Longoria P Mol Cell Biochem. 2025; .

PMID: 39827422 DOI: 10.1007/s11010-025-05205-2.

IL20RA Is the Key Factor Contributing to the Stronger Antioxidant Capacity of Rongchang Pig Sertoli Cells.

Zheng Q, Xiao L, An T, Zhang L, Long X, Wang Q Antioxidants (Basel). 2025; 13(12.

PMID: 39765872 PMC: 11727484. DOI: 10.3390/antiox13121545.

Macrophage Polarization in the Osteoarthritis Pathogenesis and Treatment.

Zou X, Xu H, Qian W Orthop Surg. 2024; 17(1):22-35.

PMID: 39638774 PMC: 11735378. DOI: 10.1111/os.14302.

References

Motshwene P, Moncrieffe M, Grossmann J, Kao C, Ayaluru M, Sandercock A . An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4. J Biol Chem. 2009; 284(37):25404-11. PMC: 2757241. DOI: 10.1074/jbc.M109.022392. View

Martinez-Nunez R, Louafi F, Sanchez-Elsner T . The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1 (IL13Ralpha1). J Biol Chem. 2010; 286(3):1786-94. PMC: 3023473. DOI: 10.1074/jbc.M110.169367. View

Sheedy F, Palsson-McDermott E, Hennessy E, Martin C, OLeary J, Ruan Q . Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2009; 11(2):141-7. DOI: 10.1038/ni.1828. View

Driessler F, Venstrom K, Sabat R, Asadullah K, Schottelius A . Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50. Clin Exp Immunol. 2003; 135(1):64-73. PMC: 1808913. DOI: 10.1111/j.1365-2249.2004.02342.x. View

Chen J, Olsen J, Ford S, Mirza S, Walker A, Murphy J . A new isoform of interleukin-3 receptor {alpha} with novel differentiation activity and high affinity binding mode. J Biol Chem. 2008; 284(9):5763-73. DOI: 10.1074/jbc.M808197200. View

Saccani A, Schioppa T, Porta C, Biswas S, Nebuloni M, Vago L . p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 2006; 66(23):11432-40. DOI: 10.1158/0008-5472.CAN-06-1867. View

Semenza G . Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med. 2010; 2(3):336-361. DOI: 10.1002/wsbm.69. View

Liu G, Friggeri A, Yang Y, Park Y, Tsuruta Y, Abraham E . miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc Natl Acad Sci U S A. 2009; 106(37):15819-24. PMC: 2747202. DOI: 10.1073/pnas.0901216106. View

He M, Xu Z, Ding T, Kuang D, Zheng L . MicroRNA-155 regulates inflammatory cytokine production in tumor-associated macrophages via targeting C/EBPbeta. Cell Mol Immunol. 2009; 6(5):343-52. PMC: 4003217. DOI: 10.1038/cmi.2009.45. View

10.

Noel W, Raes G, Hassanzadeh Ghassabeh G, De Baetselier P, Beschin A . Alternatively activated macrophages during parasite infections. Trends Parasitol. 2004; 20(3):126-33. DOI: 10.1016/j.pt.2004.01.004. View

11.

Squadrito M, Etzrodt M, de Palma M, Pittet M . MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol. 2013; 34(7):350-9. PMC: 3700601. DOI: 10.1016/j.it.2013.02.003. View

12.

Mantovani A, Sica A, Locati M . New vistas on macrophage differentiation and activation. Eur J Immunol. 2006; 37(1):14-6. DOI: 10.1002/eji.200636910. View

13.

Woronicz J, Gao X, Cao Z, Rothe M, Goeddel D . IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997; 278(5339):866-9. DOI: 10.1126/science.278.5339.866. View

14.

Biswas S, Mantovani A . Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010; 11(10):889-96. DOI: 10.1038/ni.1937. View

15.

Taganov K, Boldin M, Chang K, Baltimore D . NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006; 103(33):12481-6. PMC: 1567904. DOI: 10.1073/pnas.0605298103. View

16.

Martinez F, Helming L, Gordon S . Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2008; 27:451-83. DOI: 10.1146/annurev.immunol.021908.132532. View

17.

Reese T, Liang H, Tager A, Luster A, van Rooijen N, Voehringer D . Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature. 2007; 447(7140):92-6. PMC: 2527589. DOI: 10.1038/nature05746. View

18.

Jancic C, Cabrini M, Gabelloni M, Rodriguez Rodrigues C, Salamone G, Trevani A . Low extracellular pH stimulates the production of IL-1β by human monocytes. Cytokine. 2011; 57(2):258-68. DOI: 10.1016/j.cyto.2011.11.013. View

19.

Yona S, Kim K, Wolf Y, Mildner A, Varol D, Breker M . Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013; 38(1):79-91. PMC: 3908543. DOI: 10.1016/j.immuni.2012.12.001. View

20.

Croker B, Kiu H, Nicholson S . SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol. 2008; 19(4):414-22. PMC: 2597703. DOI: 10.1016/j.semcdb.2008.07.010. View