Abstract
Heterogeneity and plasticity are hallmarks of macrophages. Activated macrophages can be classified into two groups: M1 (or classically activated) and M2 (or alternatively activated) macrophages. Various pathological conditions have been associated with dynamic changes in the phenotypes of macrophages. Impaired polarization of macrophages affects the progression of several diseases including inflammation, tumour progression, and obesity-associated insulin resistance. Identification of the activation status of macrophages and regulations of macrophage polarization from M1 to M2 or vice versa, might serve as novel diagnostic or therapeutic approaches for various diseases. Many signalling molecules, transcription factors, epigenetic modifiers, and miRNAs (microRNAs) are known to regulate macrophage polarization and activation. Here we show that phosphatase and PTEN (phosphatase and tensin homologue deleted on chromosome 10) and SHIP1 (Src homology 2-containing inositol phosphatase 1), which dephosphorylate second messenger PtdIns(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate), can also act as regulators of macrophage polarization and activation. We compared Pten −/− macrophages and Ship1 −/− macrophages under similar conditions in vitro and in vivo and found that they regulate macrophage polarization by different mechanisms.
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References
Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288
Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657
Cao X et al (2004) The inositol 3-phosphatase PTEN negatively regulates Fc gamma receptor signaling, but supports Toll-like receptor 4 signaling in murine peritoneal macrophages. J Immunol 172:4851–4857
Chawla A (2010) Control of macrophage activation and function by PPARs. Circ Res 106:1559–1569
Clark J et al (2011) Quantification of PtdInsP3 molecular species in cells and tissues by mass spectrometry. Nat Methods 8:267–272
Cullen PJ, Venkateswarlu K (1999) Potential regulation of ADP-ribosylation factor 6 signalling by phosphatidylinositol 3,4,5-trisphosphate. Biochem Soc Trans 27:683–689
Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657
Franke TF (2008) Intracellular signaling by Akt: bound to be specific. Sci Signal 1:pe29
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35
Gordon S, Pluddemann A, Martinez Estrada F (2014) Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev 262:36–55
Hadidi S et al (2012) Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection. Mucosal Immunol 5:535–543
Helgason CD et al (1998) Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev 12:1610–1620
Hill AA, Reid Bolus W, Hasty AH (2014) A decade of progress in adipose tissue macrophage biology. Immunol Rev 262:134–152
Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867
Itoh T, Takenawa T (2002) Phosphoinositide-binding domains: functional units for temporal and spatial regulation of intracellular signalling. Cell Signal 14:733–743
Jinushi M, Komohara Y (2015) Tumor-associated macrophages as an emerging target against tumors: creating a new path from bench to bedside. Biochim Biophys Acta 1855:123–130
Kozicky LK, Sly LM (2015) Phosphatase regulation of macrophage activation. Semin Immunol 27:276–285
Krystal G (2000) Lipid phosphatases in the immune system. Semin Immunol 12:397–403
Kuroda S et al (2008) Effective clearance of intracellular Leishmania major in vivo requires Pten in macrophages. Eur J Immunol 38:1331–1340
Kuroda E et al (2011) SHIP represses Th2 skewing by inhibiting IL-4 production from basophils. J Immunol 186:323–332
Lawrence T, Natoli G (2011) Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11:750–761
Lee S et al (2011) Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol 22:317–326
Liu G, Abraham E (2013) MicroRNAs in immune response and macrophage polarization. Arterioscler Thromb Vasc Biol 33:170–177
Liu Q et al (1999) SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev 13:786–791
Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184
Maehama T (2007) PTEN: its deregulation and tumorigenesis. Biol Pharm Bull 30:1624–1627
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185
Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483
Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969
Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737
Neele AE, Van den Bossche J, Hoeksema MA, de Winther MP (2015) Epigenetic pathways in macrophages emerge as novel targets in atherosclerosis. Eur J Pharmacol 763:79–89
Odegaard JI, Chawla A (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6:275–297
Ooms LM et al (2009) The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J 419:29–49
Porta C et al (2009) Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A 106:14978–14983
Rauh MJ et al (2005) SHIP represses the generation of alternatively activated macrophages. Immunity 23:361–374
Sahin E et al (2014) Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J Immunol 193:1717–1727
Sasaki T, Sasaki J, Sakai T, Takasuga S, Suzuki A (2007) The physiology of phosphoinositides. Biol Pharm Bull 30:1599–1604
Sasaki T et al (2009) Mammalian phosphoinositide kinases and phosphatases. Prog Lipid Res 48:307–343
Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795
Sica A et al (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355
Sly LM et al (2009) SHIP prevents lipopolysaccharide from triggering an antiviral response in mice. Blood 113:2945–2954
Stephens L, Milne L, Hawkins P (2008) Moving towards a better understanding of chemotaxis. Curr Biol 18:R485–R494
Suzuki A, Nakano T, Mak TW, Sasaki T (2008) Portrait of PTEN: messages from mutant mice. Cancer Sci 99:209–213
Takeda N et al (2010) Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev 24:491–501
Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11:329–341
Waidmann O et al (2013) Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma. J Hepatol 59:769–779
Welch HC (2015) Regulation and function of P-Rex family Rac-GEFs. Small GTPases 6:49–70
Wymann MP, Pirola L (1998) Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1436:127–150
Yue S et al (2014) Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation. J Immunol 192:5343–5353
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This work was supported by Japan Science and Technology Agency (JST).
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Sasaki, J., Sasaki, T. (2016). Regulation of Chronic Inflammation by Control of Macrophage Activation and Polarization. In: Miyasaka, M., Takatsu, K. (eds) Chronic Inflammation. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56068-5_8
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DOI: https://doi.org/10.1007/978-4-431-56068-5_8
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