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Macrophage polarization and allergic asthma

  • Arjun Saradna
    Affiliations
    Division Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md

    Department of Internal Medicine, Maimonides Medical Center, Brooklyn, NY
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  • Danh C. Do
    Affiliations
    Division Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md
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  • Shruthi Kumar
    Affiliations
    Division Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md

    Bangalore Medical College and Research Institute, Bangalore, India
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  • Qing-Ling Fu
    Affiliations
    Division Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md

    Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Peisong Gao
    Correspondence
    Reprint requests: Peisong Gao, Division Allergy and Clinical Immunology, 5501 Hopkins Bayview Circle, Room 3B.71, Baltimore, MD 21224
    Affiliations
    Division Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md
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Published:October 06, 2017DOI:https://doi.org/10.1016/j.trsl.2017.09.002
      Allergic asthma is associated with airway inflammation and airway hyperresponsiveness. Macrophage polarization has been shown to have a profound impact on asthma pathogenesis. On exposure to local microenvironments, recruited macrophages can be polarized into either classically activated (or M1) or alternatively activated (or M2) phenotypes. Macrophage polarization has been heavily associated with development of asthma. The process of regulation of macrophage polarization involves an intricate interplay between various cytokines, chemokines, transcriptional factors, and immune-regulatory cells. Different signals from the microenvironment are controlled by different receptors on the macrophages to initiate various macrophage polarization pathways. Most importantly, there is an increased attention on the epigenetic changes (eg, microRNAs, DNA methylation, and histone modification) that impact macrophage functional responses and M1/M2 polarization through modulating cellular signaling and signature gene expression. Thus, modulation of macrophage phenotypes through molecular intervention by targeting some of those potential macrophage regulators may have therapeutic potential in the treatment of allergic asthma and other allergic diseases. In this review, we will discuss the origin of macrophages, characterization of macrophages, macrophage polarization in asthma, and the underlying mechanisms regarding allergen-induced macrophage polarization with emphasis on the regulation of epigenetics, which will provide new insights into the therapeutic strategy for asthma.

      Abbreviations:

      AhR (aryl hydrocarbon receptor), DMR (differentially methylated region), DNMT (DNA methyltransferases), HAT (histone acetyltransferase), HDAC (deacetylation occurs by histone deacetylase), HDM (house dust mite), ILC2 (innate lymphoid cells), IM (interstitial macrophages), M1 (classically activated macrophage), M2 (alternatively activated macrophage), miRNA (microRNA), Mo-AMs (monocyte-derived alveolar macrophages), MSC (mesenchymal stem cells), RES (reticulo-endothelial system), TR-AMs (tissue-resident alveolar macrophages)
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      References

        • Burbank A.J.
        • Sood A.K.
        • Kesic M.J.
        • Peden D.B.
        • Hernandez M.L.
        Environmental determinants of allergy and asthma in early life.
        J Allergy Clin Immunol. 2017; 140: 1-2
        • Togias A.
        • Fenton M.J.
        • Gergen P.J.
        • Rotrosen D.
        • Fauci A.S.
        Asthma in the inner city: the perspective of the National Institute of Allergy and Infectious Diseases.
        J Allergy Clin Immunol. 2010; 125: 540-544
        • Gergen P.J.
        • Togias A.
        Inner city asthma.
        Immunol Allergy Clin N Am. 2015; 35: 101-114
        • Sohn M.H.
        • Kim K.E.
        The cockroach and allergic diseases.
        Allergy Asthma Immunol Res. 2012; 4: 264-269
        • Olmedo O.
        • Goldstein I.F.
        • Acosta L.
        • et al.
        Neighborhood differences in exposure and sensitization to cockroach, mouse, dust mite, cat, and dog allergens in New York City.
        J Allergy Clin Immunol. 2011; 128: 284-292 e7
        • Do D.C.
        • Zhao Y.
        • Gao P.
        Cockroach allergen exposure and risk of asthma.
        Allergy. 2016; 71: 463-474
        • Cai Y.
        • Sugimoto C.
        • Arainga M.
        • Alvarez X.
        • Didier E.S.
        • Kuroda M.J.
        In vivo characterization of alveolar and interstitial lung macrophages in rhesus macaques: implications for understanding lung disease in humans.
        J Immunol. 2014; 192: 2821-2829
        • Fehervari Z.
        Alveolar macrophages in asthma.
        Nat Immunol. 2014; 16: 64
        • Lee Y.G.
        • Jeong J.J.
        • Nyenhuis S.
        • et al.
        Recruited alveolar macrophages, in response to airway epithelial-derived monocyte chemoattractant protein 1/CCl2, regulate airway inflammation and remodeling in allergic asthma.
        Am J Respir Cell Mol Biol. 2015; 52: 772-784
        • Epelman S.
        • Lavine K.J.
        • Randolph G.J.
        Origin and functions of tissue macrophages.
        Immunity. 2014; 41: 21-35
        • Li H.
        • Ciric B.
        • Yang J.
        • et al.
        Intravenous tolerance modulates macrophage classical activation and antigen presentation in experimental autoimmune encephalomyelitis.
        J Neuroimmunol. 2009; 208: 54-60
        • Gordon S.
        Alternative activation of macrophages.
        Nat Rev Immunol. 2003; 3: 23-35
        • Liu C.
        • Li Y.
        • Yu J.
        • et al.
        Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil.
        PLoS One. 2013; 8: e54841
        • Sica A.
        • Mantovani A.
        Macrophage plasticity and polarization: in vivo veritas.
        J Clin Invest. 2012; 122: 787-795
        • Spence S.
        • Fitzsimons A.
        • Boyd C.R.
        • et al.
        Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization.
        Immunity. 2013; 38: 66-78
        • Biswas S.K.
        • Mantovani A.
        Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.
        Nat Immunol. 2010; 11: 889-896
        • Mantovani A.
        • Biswas S.K.
        • Galdiero M.R.
        • Sica A.
        • Locati M.
        Macrophage plasticity and polarization in tissue repair and remodelling.
        J Pathol. 2013; 229: 176-185
        • Melgert B.N.
        • ten Hacken N.H.
        • Rutgers B.
        • Timens W.
        • Postma D.S.
        • Hylkema M.N.
        More alternative activation of macrophages in lungs of asthmatic patients.
        J Allergy Clin Immunol. 2011; 127: 831-833
        • Girodet P.-O.O.
        • Nguyen D.
        • Mancini J.D.
        • et al.
        Alternative macrophage activation is increased in asthma.
        Am J Respir Cell Mol Biol. 2016; 55: 467-475
        • Hazlett L.D.
        • McClellan S.A.
        • Barrett R.P.
        • et al.
        IL-33 shifts macrophage polarization, promoting resistance against Pseudomonas aeruginosa keratitis.
        Invest Ophthalmol Vis Sci. 2010; 51: 1524-1532
        • Wynn T.A.
        • Chawla A.
        • Pollard J.W.
        Macrophage biology in development, homeostasis and disease.
        Nature. 2013; 496: 445-455
        • Sierra-Filardi E.
        • Nieto C.
        • Dominguez-Soto A.
        • et al.
        CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile.
        J Immunol. 2014; 192: 3858-3867
        • Jiang Z.
        • Zhu L.
        Update on the role of alternatively activated macrophages in asthma.
        J Asthma Allergy. 2016; 9: 101-107
        • Carson W.F.
        • Salter-Green S.E.
        • Scola M.M.
        • Joshi A.
        • Gallagher K.A.
        • Kunkel S.L.
        Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6.
        Cell Immunol. 2017; 314: 63-72
        • Murray P.J.
        Macrophage polarization.
        Annu Rev Physiol. 2017; 79: 541-566
        • Hinde K.
        • Lewis Z.T.
        MICROBIOTA. Mother's littlest helpers.
        Science. 2015; 348: 1427-1428
        • Gordon S.
        Elie Metchnikoff: father of natural immunity.
        Eur J Immunol. 2008; 38: 3257-3264
        • Normann S.J.
        Function of the Reticuloendothelial system IV. Evidence for two types of Particle-induced Reticuloendothelial Paralysis.
        Infect Immun. 1970; 1: 327-333
        • van Furth R.
        • Cohn Z.A.
        • Hirsch J.G.
        • Humphrey J.H.
        • Spector W.G.
        • Langevoort H.L.
        The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells.
        Bull World Health Organ. 1972; 46: 845-852
        • Carrel A.
        • Ebeling A.H.
        The Fundamental properties of the Fibroblast and the macrophage: I. The Fibroblast.
        J Exp Med. 1926; 44: 261-284
        • Marchesi V.T.
        • Florey H.W.
        Electron micrographic observations on the emigration of leucocytes.
        Q J Exp Physiol Cogn Med Sci. 1960; 45: 343-348
        • Volkman A.
        • Gowans J.L.
        The origin of macrophages from bone marrow in the Rat.
        Br J Exp Pathol. 1965; 46: 62-70
        • Yona S.
        • Kim K.W.
        • Wolf Y.
        • et al.
        Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis.
        Immunity. 2013; 38: 79-91
        • Van den Bossche J.
        • Malissen B.
        • Mantovani A.
        • De Baetselier P.
        • Van Ginderachter J.A.
        Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs.
        Blood. 2012; 119: 1623-1633
        • Satoh T.
        • Kidoya H.
        • Naito H.
        • et al.
        Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages.
        Nature. 2013; 495: 524-528
        • McCubbrey A.L.
        • Barthel L.
        • Mohning M.P.
        • et al.
        Deletion of c-FLIP from CD11bhi macrophages Prevents development of bleomycin-induced lung fibrosis.
        Am J Respir Cell Mol Biol. 2017; (http://dx.doi.org/10.1165/rcmb.2017-0154OC [Epub ahead of print])
        • Guilliams M.
        • De Kleer I.
        • Henri S.
        • et al.
        Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF.
        J Exp Med. 2013; 210: 1977-1992
        • Okuma T.
        • Terasaki Y.
        • Kaikita K.
        • et al.
        C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases.
        J Pathol. 2004; 204: 594-604
        • Tsou C.L.
        • Peters W.
        • Si Y.
        • et al.
        Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites.
        J Clin Invest. 2007; 117: 902-909
        • Hashimoto D.
        • Chow A.
        • Noizat C.
        • et al.
        Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes.
        Immunity. 2013; 38: 792-804
        • Misharin A.V.
        • Morales-Nebreda L.
        • Reyfman P.A.
        • et al.
        Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.
        J Exp Med. 2017; 214: 2387-2404
        • Gibbings S.L.
        • Thomas S.M.
        • Atif S.M.
        • et al.
        Three unique interstitial macrophages in the murine lung at Steady state.
        Am J Respir Cell Mol Biol. 2017; 57: 66-76
        • Ji W.J.
        • Ma Y.Q.
        • Zhou X.
        • et al.
        Temporal and spatial characterization of mononuclear phagocytes in circulating, lung alveolar and interstitial compartments in a mouse model of bleomycin-induced pulmonary injury.
        J Immunol Methods. 2014; 403: 7-16
        • Zaslona Z.
        • Przybranowski S.
        • Wilke C.
        • et al.
        Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma.
        J Immunol. 2014; 193: 4245-4253
        • Draijer C.
        • Peters-Golden M.
        Alveolar Macrophages in Allergic Asthma: the Forgotten Cell Awakes.
        Curr Allergy Asthma Rep. 2017; 17: 12
        • Sierra-Filardi E.
        • Vega M.A.
        • Sanchez-Mateos P.
        • Corbi A.L.
        • Puig-Kroger A.
        Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release.
        Immunobiology. 2010; 215: 788-795
        • van Tits L.J.
        • Stienstra R.
        • van Lent P.L.
        • Netea M.G.
        • Joosten L.A.
        • Stalenhoef A.F.
        Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: a crucial role for Kruppel-like factor 2.
        Atherosclerosis. 2011; 214: 345-349
        • Tian S.
        • Zhang L.
        • Tang J.
        • Guo X.
        • Dong K.
        • Chen S.Y.
        HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury.
        Am J Physiol Renal Physiol. 2015; 308: F69-75
        • Shivshankar P.
        • Halade G.V.
        • Calhoun C.
        • et al.
        Caveolin-1 deletion exacerbates cardiac interstitial fibrosis by promoting M2 macrophage activation in mice after myocardial infarction.
        J Mol Cell Cardiol. 2014; 76: 84-93
        • Robbe P.
        • Draijer C.
        • Borg T.R.
        • et al.
        Distinct macrophage phenotypes in allergic and nonallergic lung inflammation.
        Am J Physiol Lung Cell Mol Physiol. 2015; 308: L358-67
        • Oriss T.B.
        • Raundhal M.
        • Morse C.
        • et al.
        IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice.
        JCI Insight. 2017; 2 (http://dx.doi.org/10.1172/jci.insight.91019 [Epub ahead of print])
        • Mantovani A.
        • Sica A.
        • Sozzani S.
        • Allavena P.
        • Vecchi A.
        • Locati M.
        The chemokine system in diverse forms of macrophage activation and polarization.
        Trends Immunol. 2004; 25: 677-686
        • Zhong B.
        • Yang X.
        • Sun Q.
        • et al.
        Pdcd4 modulates markers of macrophage alternative activation and airway remodeling in antigen-induced pulmonary inflammation.
        J Leukoc Biol. 2014; 96: 1065-1075
        • Bhatia S.
        • Fei M.
        • Yarlagadda M.
        • et al.
        Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype.
        PLoS One. 2011; 6: e15943
        • Raes G.
        • De Baetselier P.
        • Noel W.
        • Beschin A.
        • Brombacher F.
        • Hassanzadeh Gh G.
        Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages.
        J Leukoc Biol. 2002; 71: 597-602
        • Raes G.
        • Noel W.
        • Beschin A.
        • Brys L.
        • de Baetselier P.
        • Hassanzadeh G.H.
        FIZZ1 and Ym as tools to discriminate between differentially activated macrophages.
        Dev Immunol. 2002; 9: 151-159
        • Byers D.E.
        • Holtzman M.J.
        Alternatively activated macrophages and airway disease.
        Chest. 2011; 140: 768-774
        • Siddiqui S.
        • Secor Jr., E.R.
        • Silbart L.K.
        Broncho-alveolar macrophages express chemokines associated with leukocyte migration in a mouse model of asthma.
        Cell Immunol. 2013; 281: 159-169
        • Lu J.
        • Cao Q.
        • Zheng D.
        • et al.
        Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease.
        Kidney Int. 2013; 84: 745-755
        • Nabe T.
        • Wakamori H.
        • Yano C.
        • et al.
        Production of interleukin (IL)-33 in the lungs during multiple antigen challenge-induced airway inflammation in mice, and its modulation by a glucocorticoid.
        Eur J Pharmacol. 2015; 757: 34-41
        • Joshi A.D.
        • Oak S.R.
        • Hartigan A.J.
        • et al.
        Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages.
        BMC Immunol. 2010; 11: 52
        • Kurowska-Stolarska M.
        • Stolarski B.
        • Kewin P.
        • et al.
        IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation.
        J Immunol. 2009; 183: 6469-6477
        • Tiemessen M.M.
        • Jagger A.L.
        • Evans H.G.
        • van Herwijnen M.J.
        • John S.
        • Taams L.S.
        CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages.
        Proc Natl Acad Sci U S A. 2007; 104: 19446-19451
        • Wu D.
        • Molofsky A.B.
        • Liang H.E.
        • et al.
        Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.
        Science. 2011; 332: 243-247
        • Molofsky A.B.
        • Nussbaum J.C.
        • Liang H.E.
        • et al.
        Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages.
        J Exp Med. 2013; 210: 535-549
        • Song X.
        • Xie S.
        • Lu K.
        • Wang C.
        Mesenchymal stem cells Alleviate experimental asthma by inducing polarization of alveolar macrophages.
        Inflammation. 2015; 38: 485-492
        • Braza F.
        • Dirou S.
        • Forest V.
        • et al.
        Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma.
        Stem Cells. 2016; 34: 1836-1845
        • Sica A.
        • Erreni M.
        • Allavena P.
        • Porta C.
        Macrophage polarization in pathology.
        Cell Mol Life Sci. 2015; 72: 4111-4126
        • Mills C.D.
        • Ley K.
        M1 and M2 macrophages: the chicken and the egg of immunity.
        J Innate Immun. 2014; 6: 716-726
        • Toshchakov V.
        • Jones B.W.
        • Perera P.Y.
        • et al.
        TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages.
        Nat Immunol. 2002; 3: 392-398
        • Krausgruber T.
        • Blazek K.
        • Smallie T.
        • et al.
        IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.
        Nat Immunol. 2011; 12: 231-238
        • Ni Gabhann J.
        • Hams E.
        • Smith S.
        • et al.
        Btk regulates macrophage polarization in response to lipopolysaccharide.
        PLoS One. 2014; 9: e85834
        • Eun S.Y.
        • Seo J.
        • Park S.W.
        • Lee J.H.
        • Chang K.C.
        • Kim H.J.
        LPS potentiates nucleotide-induced inflammatory gene expression in macrophages via the upregulation of P2Y2 receptor.
        Int Immunopharmacol. 2014; 18: 270-276
        • Arnold C.E.
        • Whyte C.S.
        • Gordon P.
        • Barker R.N.
        • Rees A.J.
        • Wilson H.M.
        A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo.
        Immunology. 2014; 141: 96-110
        • Sierra-Filardi E.
        • Puig-Kroger A.
        • Blanco F.J.
        • et al.
        Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers.
        Blood. 2011; 117: 5092-5101
        • Sica A.
        • Bronte V.
        Altered macrophage differentiation and immune dysfunction in tumor development.
        J Clin Invest. 2007; 117: 1155-1166
        • Chawla A.
        Control of macrophage activation and function by PPARs.
        Circ Res. 2010; 106: 1559-1569
        • Bouhlel M.A.
        • Derudas B.
        • Rigamonti E.
        • et al.
        PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.
        Cell Metab. 2007; 6: 137-143
        • Luzina I.G.
        • Keegan A.D.
        • Heller N.M.
        • Rook G.A.
        • Shea-Donohue T.
        • Atamas S.P.
        Regulation of inflammation by interleukin-4: a review of “alternatives”.
        J Leukoc Biol. 2012; 92: 753-764
        • Liao X.
        • Sharma N.
        • Kapadia F.
        • et al.
        Kruppel-like factor 4 regulates macrophage polarization.
        J Clin Invest. 2011; 121: 2736-2749
        • Emara M.
        • Royer P.J.
        • Abbas Z.
        • et al.
        Recognition of the major cat allergen Fel d 1 through the cysteine-rich domain of the mannose receptor determines its allergenicity.
        J Biol Chem. 2011; 286: 13033-13040
        • Royer P.J.
        • Emara M.
        • Yang C.
        • et al.
        The mannose receptor mediates the uptake of diverse native allergens by dendritic cells and determines allergen-induced T cell polarization through modulation of IDO activity.
        J Immunol. 2010; 185: 1522-1531
        • Zhou Y.
        • Do D.C.
        • Ishmael F.T.
        • et al.
        Mannose receptor regulates macrophage polarization and allergic inflammation through MiR-511-3p.
        J Allergy Clin Immunol. 2017; (http://dx.doi.org/10.1016/j.jaci.2017.04.049 [Epub ahead of print])
        • Zhou D.
        • Yang K.
        • Chen L.
        • et al.
        Promising landscape for regulating macrophage polarization: epigenetic viewpoint.
        Oncotarget. 2017; 8: 57693-57706
        • Van den Bossche J.
        • Neele A.E.
        • Hoeksema M.A.
        • de Winther M.P.
        Macrophage polarization: the epigenetic point of view.
        Curr Opin Lipidol. 2014; 25: 367-373
        • Seibold M.A.
        • Schwartz D.A.
        The lung: the natural boundary between nature and nurture.
        Annu Rev Physiol. 2011; 73: 457-478
        • Bartel D.P.
        MicroRNAs: target recognition and regulatory functions.
        Cell. 2009; 136: 215-233
        • Lu T.X.
        • Hartner J.
        • Lim E.J.
        • et al.
        MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity.
        J Immunol. 2011; 187: 3362-3373
        • Simpson L.J.
        • Patel S.
        • Bhakta N.R.
        • et al.
        A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production.
        Nat Immunol. 2014; 15: 1162-1170
        • Bazzoni F.
        • Rossato M.
        • Fabbri M.
        • et al.
        Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals.
        Proc Natl Acad Sci U S A. 2009; 106: 5282-5287
        • Das A.
        • Ganesh K.
        • Khanna S.
        • Sen C.K.
        • Roy S.
        Engulfment of apoptotic cells by macrophages: a role of microRNA-21 in the resolution of wound inflammation.
        J Immunol. 2014; 192: 1120-1129
        • Mattes J.
        • Collison A.
        • Plank M.
        • Phipps S.
        • Foster P.S.
        Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease.
        Proc Natl Acad Sci U S A. 2009; 106: 18704-18709
        • Solberg O.D.
        • Ostrin E.J.
        • Love M.I.
        • et al.
        Airway epithelial miRNA expression is altered in asthma.
        Am J Respir Crit Care Med. 2012; 186: 965-974
        • Comer B.S.
        • Camoretti-Mercado B.
        • Kogut P.C.
        • Halayko A.J.
        • Solway J.
        • Gerthoffer W.T.
        MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle.
        Am J Physiol Lung Cell Mol Physiol. 2014; 307: L727-34
        • Melton D.W.
        • Lei X.
        • Gelfond J.A.
        • Shireman P.K.
        Dynamic macrophage polarization-specific miRNA patterns reveal increased soluble VEGF receptor 1 by miR-125a-5p inhibition.
        Physiol Genomics. 2016; 48: 345-360
        • Lu T.X.
        • Munitz A.
        • Rothenberg M.E.
        MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression.
        J Immunol. 2009; 182: 4994-5002
        • Martinez-Nunez R.T.
        • 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. 2011; 286: 1786-1794
        • Graff J.W.
        • Dickson A.M.
        • Clay G.
        • McCaffrey A.P.
        • Wilson M.E.
        Identifying functional microRNAs in macrophages with polarized phenotypes.
        J Biol Chem. 2012; 287: 21816-21825
        • Lawrence T.
        • Natoli G.
        Transcriptional regulation of macrophage polarization: enabling diversity with identity.
        Nat Rev Immunol. 2011; 11: 750-761
        • Yoon W.H.
        • Meinhardt H.
        • Montell D.J.
        miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold.
        Nat Cell Biol. 2011; 13: 1062-1069
        • Wu S.C.
        • Zhang Y.
        Active DNA demethylation: many roads lead to Rome.
        Nat Rev Mol Cell Biol. 2010; 11: 607-620
        • Morales E.
        • Bustamante M.
        • Vilahur N.
        • et al.
        DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood.
        Am J Respir Crit Care Med. 2012; 185: 937-943
        • Breton C.V.
        • Byun H.M.
        • Wang X.
        • Salam M.T.
        • Siegmund K.
        • Gilliland F.D.
        DNA methylation in the arginase-nitric oxide synthase pathway is associated with exhaled nitric oxide in children with asthma.
        Am J Respir Crit Care Med. 2011; 184: 191-197
        • Yang I.V.
        • Pedersen B.S.
        • Liu A.
        • et al.
        DNA methylation and childhood asthma in the inner city.
        J Allergy Clin Immunol. 2015; 136: 69-80
        • Hardbower D.M.
        • Asim M.
        • Luis P.B.
        • et al.
        Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications.
        Proc Natl Acad Sci U S A. 2017; 114: E751-60
        • Kabesch M.
        • Adcock I.M.
        Epigenetics in asthma and COPD.
        Biochimie. 2012; 94: 2231-2241
        • Barnes P.J.
        Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.
        J Allergy Clin Immunol. 2013; 131: 636-645
        • Chen X.
        • Barozzi I.
        • Termanini A.
        • et al.
        Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages.
        Proc Natl Acad Sci U S A. 2012; 109: E2865-74
        • Yang X.
        • Wang X.
        • Liu D.
        • Yu L.
        • Xue B.
        • Shi H.
        Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b.
        Mol Endocrinol. 2014; 28: 565-574
        • Kittan N.A.
        • Allen R.M.
        • Dhaliwal A.
        • et al.
        Cytokine induced phenotypic and epigenetic signatures are key to establishing specific macrophage phenotypes.
        PLoS One. 2013; 8: e78045
        • Thangavel J.
        • Samanta S.
        • Rajasingh S.
        • et al.
        Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury.
        J Cell Sci. 2015; 128: 3094-3105
        • Cokus S.J.
        • Feng S.
        • Zhang X.
        • et al.
        Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning.
        Nature. 2008; 452: 215-219
        • Satoh T.
        • Takeuchi O.
        • Vandenbon A.
        • et al.
        The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.
        Nat Immunol. 2010; 11: 936-944
        • Ishii M.
        • Wen H.
        • Corsa C.A.
        • et al.
        Epigenetic regulation of the alternatively activated macrophage phenotype.
        Blood. 2009; 114: 3244-3254
        • Climaco-Arvizu S.
        • Domínguez-Acosta O.
        • Cabañas-Cortés M.A.A.
        • et al.
        Aryl hydrocarbon receptor influences nitric oxide and arginine production and alters M1/M2 macrophage polarization.
        Life Sci. 2016; 155: 76-84
        • Liao W.-T.T.
        • Lu J.-H.H.
        • Wang W.-T.T.
        • Hung C.-H.H.
        • Sheu C.-C.C.
        • Huang S.-K.K.
        Epigenetic synergism between interleukin-4 and aryl-hydrocarbon receptor in human macrophages.
        J Mol Med (Berl). 2017; 95: 395-404
        • Kruidenier L.
        • Chung C.W.
        • Cheng Z.
        • et al.
        A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
        Nature. 2012; 488: 404-408
        • Xu G.
        • Liu G.
        • Xiong S.
        • Liu H.
        • Chen X.
        • Zheng B.
        The histone methyltransferase Smyd2 is a negative regulator of macrophage activation by suppressing interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) production.
        J Biol Chem. 2015; 290: 5414-5423
        • Chen C.H.
        • Wang C.Z.
        • Wang Y.H.
        • et al.
        Effects of low-level laser therapy on M1-related cytokine expression in monocytes via histone modification.
        Mediators Inflamm. 2014; 2014: 625048
        • Mullican S.E.
        • Gaddis C.A.
        • Alenghat T.
        • et al.
        Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation.
        Genes Dev. 2011; 25: 2480-2488
        • Yang J.
        • Yin S.
        • Bi F.
        • et al.
        TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis.
        J Mol Med (Berl). 2017; 95: 273-285
        • Ji J.
        • Shu D.
        • Zheng M.
        • et al.
        Microbial metabolite butyrate facilitates M2 macrophage polarization and function.
        Sci Rep. 2016; 6: 24838
        • Fordham J.
        • Naqvi A.R.
        • Nares S.
        miR-24 regulates macrophage polarization and plasticity.
        J Clin Cell Immunol. 2015; 6 (http://dx.doi.org/10.4172/2155-9899.1000362)
        • Jiang P.
        • Liu R.
        • Zheng Y.
        • et al.
        MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages.
        Exp Cell Res. 2012; 318: 1175-1184
        • Plank M.W.
        • Maltby S.
        • Tay H.L.
        • et al.
        MicroRNA expression is altered in an Ovalbumin-induced asthma model and targeting miR-155 with Antagomirs reveals cellular Specificity.
        PLoS One. 2015; 10: e0144810
        • Sonkoly E.
        • Janson P.
        • Majuri M.L.
        • et al.
        MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4.
        J Allergy Clin Immunol. 2010; 126 (589.e1–589.e20): 581
        • Malmhall C.
        • Alawieh S.
        • Lu Y.
        • et al.
        MicroRNA-155 is essential for T(H)2-mediated allergen-induced eosinophilic inflammation in the lung.
        J Allergy Clin Immunol. 2014; 133 (1438.e1–1438.e7): 1429-1438
        • Johansson K.
        • Malmhäll C.
        • Ramos-Ramírez P.
        • Rådinger M.
        MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation.
        J Allergy Clin Immunol. 2017; 139: 1007
        • Okoye I.S.
        • Czieso S.
        • Ktistaki E.
        • et al.
        Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity.
        Proc Natl Acad Sci U S A. 2014; 111: E3081-90
        • Zech A.
        • Ayata C.K.
        • Pankratz F.
        • et al.
        MicroRNA-155 modulates P2R signaling and Th2 priming of dendritic cells during allergic airway inflammation in mice.
        Allergy. 2015; 70: 1121-1129
        • Zhou H.
        • Li J.
        • Gao P.
        • Wang Q.
        • Zhang J.
        miR-155: a novel target in allergic asthma.
        Int J Mol Sci. 2016; 17
        • Comer B.S.
        • Camoretti-Mercado B.
        • Kogut P.C.
        • Halayko A.J.
        • Solway J.
        • Gerthoffer W.T.
        Cyclooxygenase-2 and microRNA-155 expression are elevated in asthmatic airway smooth muscle cells.
        Am J Respir Cell Mol Biol. 2015; 52: 438-447
        • Ruggiero T.
        • Trabucchi M.
        • De Santa F.
        • et al.
        LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages.
        FASEB J. 2009; 23: 2898-2908
        • Louafi F.
        • Martinez-Nunez R.T.
        • Sanchez-Elsner T.
        MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-{beta}.
        J Biol Chem. 2010; 285: 41328-41336
        • Ye J.
        • Guo R.
        • Shi Y.
        • Qi F.
        • Guo C.
        • Yang L.
        miR-155 regulated inflammation response by the SOCS1-STAT3-PDCD4 Axis in Atherogenesis.
        Mediators Inflamm. 2016; 2016: 8060182
        • Lu Z.J.
        • Wu J.J.
        • Jiang W.L.
        • et al.
        MicroRNA-155 promotes the pathogenesis of experimental colitis by repressing SHIP-1 expression.
        World J Gastroenterol. 2017; 23: 976-985
        • Nazari-Jahantigh M.
        • Wei Y.
        • Noels H.
        • et al.
        MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages.
        J Clin Invest. 2012; 122: 4190-4202
        • Arranz A.
        • Doxaki C.
        • Vergadi E.
        • et al.
        Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization.
        Proc Natl Acad Sci U S A. 2012; 109: 9517-9522
        • Li X.
        • Kong D.
        • Chen H.
        • et al.
        miR-155 acts as an anti-inflammatory factor in atherosclerosis-associated foam cell formation by repressing calcium-regulated heat stable protein 1.
        Sci Rep. 2016; 6: 21789
        • Panganiban R.P.
        • Wang Y.
        • Howrylak J.
        • et al.
        Circulating microRNAs as biomarkers in patients with allergic rhinitis and asthma.
        J Allergy Clin Immunol. 2016; 137: 1423-1432
        • Malmhäll C.
        • Johansson K.
        • Winkler C.
        • Alawieh S.
        • Ekerljung L.
        • Rådinger M.
        Altered miR-155 expression in allergic asthmatic airways.
        Scand J Immunol. 2017; 85: 300-307
        • Huang C.
        • Liu X.J.
        • QunZhou
        • et al.
        MiR-146a modulates macrophage polarization by inhibiting Notch1 pathway in RAW264.7 macrophages.
        Int Immunopharmacol. 2016; 32: 46-54
        • Taganov K.D.
        • Boldin M.P.
        • Chang K.J.
        • 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: 12481-12486
        • Vergadi E.
        • Vaporidi K.
        • Theodorakis E.E.
        • et al.
        Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR-146a induction in mice.
        J Immunol. 2014; 192: 394-406
        • Zeng Z.
        • Gong H.
        • Li Y.
        • et al.
        Upregulation of miR-146a contributes to the suppression of inflammatory responses in LPS-induced acute lung injury.
        Exp Lung Res. 2013; 39: 275-282
        • Peng L.
        • Zhang H.
        • Hao Y.
        • et al.
        Reprogramming macrophage orientation by microRNA 146b targeting transcription factor IRF5.
        EBioMedicine. 2016; 14: 83-96
        • Curtale G.
        • Mirolo M.
        • Renzi T.A.
        • Rossato M.
        • Bazzoni F.
        • Locati M.
        Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b.
        Proc Natl Acad Sci U S A. 2013; 110: 11499-11504
        • Zhang W.
        • Liu H.
        • Liu W.
        • Liu Y.
        • Xu J.
        Polycomb-mediated loss of microRNA let-7c determines inflammatory macrophage polarization via PAK1-dependent NF-kappaB pathway.
        Cell Death Differ. 2015; 22: 287-297
        • Banerjee S.
        • Xie N.
        • Cui H.
        • et al.
        MicroRNA let-7c regulates macrophage polarization.
        J Immunol. 2013; 190: 6542-6549
        • Caescu C.I.
        • Guo X.
        • Tesfa L.
        • et al.
        Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21.
        Blood. 2015; 125: e1-3
        • Smallie T.
        • Ricchetti G.
        • Horwood N.J.
        • Feldmann M.
        • Clark A.R.
        • Williams L.M.
        IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages.
        J Exp Med. 2010; 207: 2081-2088
        • Squadrito M.L.
        • Pucci F.
        • Magri L.
        • et al.
        miR-511-3p modulates genetic programs of tumor-associated macrophages.
        Cell Rep. 2012; 1: 141-154
        • Squadrito M.L.
        • Etzrodt M.
        • De Palma M.
        • Pittet M.J.
        MicroRNA-mediated control of macrophages and its implications for cancer.
        Trends Immunol. 2013; 34: 350-359
        • Heinsbroek S.E.
        • Squadrito M.L.
        • Schilderink R.
        • et al.
        miR-511-3p, embedded in the macrophage mannose receptor gene, contributes to intestinal inflammation.
        Mucosal Immunol. 2016; 9: 960-973
        • Kwon N.H.
        • Kim J.S.
        • Lee J.Y.
        • Oh M.J.
        • Choi D.C.
        DNA methylation and the expression of IL-4 and IFN-gamma promoter genes in patients with bronchial asthma.
        J Clin Immunol. 2008; 28: 139-146
        • Runyon R.S.
        • Cachola L.M.
        • Rajeshuni N.
        • et al.
        Asthma discordance in twins is linked to epigenetic modifications of T cells.
        PLoS One. 2012; 7: e48796
        • Yang I.V.
        • Lozupone C.A.
        • Schwartz D.A.
        The environment, epigenome, and asthma.
        J Allergy Clin Immunol. 2017; 140: 14-23
        • Iwanowycz S.
        • Wang J.
        • Altomare D.
        • Hui Y.
        • Fan D.
        Emodin Bidirectionally modulates macrophage polarization and epigenetically regulates macrophage memory.
        J Biol Chem. 2016; 291: 11491-11503