白细胞介素4和白细胞介素13与M2型肺泡巨噬细胞在肺纤维化中的作用研究进展
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摘要
2型辅助性T细胞(Th2)是CD4+T细胞经抗原刺激后分化的细胞群,其分泌的白细胞介素4(IL-4)/IL-13作用于巨噬细胞,使其经"替代激活"活化为M2型巨噬细胞,从而发挥特定作用;肺组织在受到抗原持续刺激后,存在于肺泡及间充质中的巨噬细胞在经Th2细胞分泌的IL-4和IL-13激活形成M2型肺泡巨噬细胞,从而参与肺纤维化(PF)的进程,可见M2肺泡巨噬细胞在PF中起着重要的作用。本综述以PF为背景,探讨Th2型细胞因子IL-4和IL-13在PF中的作用,M2型肺泡巨噬细胞的抗炎和促纤维化作用,IL-4和IL-13受体在治疗PF中的作用,IL-4和IL-13激活的M2型肺泡巨噬细胞对PF的双重作用,为抗PF药物研究提供思路。
Type-2 helper T cells(Th2) are a group of cells differentiated from CD4+T cells after antigen stimulation. Interleukin-4(IL-4) and IL-13 secreted by Th2 cells act on macrophages and activate them into M2 macrophages via "alternative activation". When lung tissue is continuously stimulated by the antigen, the alveolar and interstitial macrophages are activated by IL-4 and IL-13 secreted by Th2 cells to form M2 type alveolar macrophages, thereby participating in pulmonary fibrosis(PF). The process shows that M2 alveolar macrophages play an important role in PF. In this review, we investigated the role of cytokine IL-4 and IL-13 in PF, the anti-inflammatory and profibrotic effects of M2 alveolar macrophages, the role of IL-4 and IL-13 receptors in the treatment of PF and the dual role of M2 alveolar macrophages activated by IL-4 and IL-13 in PF. Hoping to spark novel ideas for the study of anti-PF drugs.
Type-2 helper T cells(Th2) are a group of cells differentiated from CD4+T cells after antigen stimulation. Interleukin-4(IL-4) and IL-13 secreted by Th2 cells act on macrophages and activate them into M2 macrophages via "alternative activation". When lung tissue is continuously stimulated by the antigen, the alveolar and interstitial macrophages are activated by IL-4 and IL-13 secreted by Th2 cells to form M2 type alveolar macrophages, thereby participating in pulmonary fibrosis(PF). The process shows that M2 alveolar macrophages play an important role in PF. In this review, we investigated the role of cytokine IL-4 and IL-13 in PF, the anti-inflammatory and profibrotic effects of M2 alveolar macrophages, the role of IL-4 and IL-13 receptors in the treatment of PF and the dual role of M2 alveolar macrophages activated by IL-4 and IL-13 in PF. Hoping to spark novel ideas for the study of anti-PF drugs.
引文
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[7]Dong X. Effect of tranilast on IL-4,IL-13 expression and pulmonary fibrosis caused by paraquate poisoning in rats(曲尼司特在大鼠百草枯中毒肺纤维化过程中IL-4、IL-13的相关性研究)[D]. Zunyi:Zunyi Medical College(遵义医学院),2014.
[8]Chen C,Zhang X,Hong ZP. Research progress in key cells and molecules in pathogenesis of pulmonary fibrosis[J]. Basic Clin Med(基础医学与临床),2018,38(9):1329-1332.
[9] Zhu L,Fu X,Chen X,Han X,Dong P. M2 macrophages induce EMT through the TGF-β/Smad2 signaling pathway[J]. Cel Biol Int,2017,41(9):960-968.
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[12] Szabo SJ,Jacobson NG,Dighe AS,Gubler U,Murphy KM. Developmental commitment to the Th2 lineage by extinction of IL-12 signaling[J]. Immunity,1995,2(6):665-675.
[13] Anthony RM,Kobayashi T,Wermeling F,Ravetch JV.Intravenous gammaglobulin suppresses inflammation through a novel Th2 pathway[J]. Nature,2011,475(7354):110-113.
[14] Palmer LD,Maloney KN,Boyd KL,Goleniewska AK,Toki S,Maxwel CN,et al. The innate immune protein S100A9 protects from Th2-mediated al ergic airway inflammation[J/OL]. Am J Respir Cell Mol Biol,2019(2019-04-03). https://www.atsjournals.org/doi/abs/10.1165/rcmb.201 8-0217OC
[15] Dong J, Ma Q. Type 2 immune mechanisms in carbon nanotube-induced lung fibrosis[J/OL]. Front Immunol,2018,9:1120(2018-05-22). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972321/
[16] Mojiri-Forushani H, Hemmati AA, Khodadadi A,Rashno M. Valsartan attenuates bleomycin-induced pulmonary fibrosis by inhibition of NF-κB expression and regulation of Th1/Th2 cytokines[J]. Immunopharmacol Immunotoxicol,2018,40(3):225-231.
[17] Singh B, Kasam RK, Sontake V, Wynn TA,Madala SK. Repetitive intradermal bleomycin injections evoke T-helper cel 2 cytokine-driven pulmonary fibrosis[J]. Am J Physiol Lung Cel Mol Physiol,2017,313(5):L796-L806.
[18] Wei Q,Sha Y,Bhattacharya A,Abdel Fattah E,Bonilla D,Jyothula SS,et al. Regulation of IL-4receptor signaling by STUB1 in lung inflammation[J].Am J Respir Crit Care Med,2014,189(1):16-29.
[19] Zhang C,Zhao H,Li BL,Fu-Gao,Liu H,Cai JM,et al. CpG-oligodeoxynucleotides may be effective for preventing ionizing radiation induced pulmonary fibrosis[J]. Toxicol Lett,2018,292:181-189.
[20] Grabarz F,Aguiar CF,Correa-Costa M,Braga TT,Hyane MI,Andrade-Oliveira V,et al. Protective role of NKT cel s and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis[J].Inflammopharmacology,2018,26(2):491-504.
[21] Arora S,Dev K,Agarwal B,Das P,Syed MA.Macrophages:their role,activation and polarization in pulmonary diseases[J]. Immunobiology,2018,223(4-5):383-396.
[22] Chávez-Galán L,Olleros ML,Vesin D,Garcia I.Much more than M1 and M2 macrophages,there are also CD169+and TCR+macrophages[J/OL].Front Immunol,2015,6:263(2015-05-26). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443739/
[23] Parisi L,Gini E,Baci D,Tremolati M,Fanuli M,Bassani B,et al. Macrophage polarization in chronic inflammatory diseases:killers or builders?[J/OL].J Immunol Res,2018,2018:8917804(2018-01-14).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821995/
[24] Kreider T,Anthony RM,Urban JF Jr,Gause WC.Alternatively activated macrophages in helminth infections[J]. Curr Opin Immunol,2007,19(4):448-453.
[25] Misharin AV,Morales-Nebreda L,Reyfman PA,Cuda CM,Walter JM,Mc Quattie-Pimentel AC,et al.Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span[J]. J Exp Med,2017,214(8):2387-2404.
[26] Baran CP,Opalek JM,Mc Maken S,Newland CA,O′Brien JM Jr,Hunter MG,et al. Important roles for macrophage colony-stimulating factor,CC chemokine ligand 2,and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis[J]. Am J Respir Crit Care Med,2007,176(1):78-89.
[27] Gundra UM,Girgis NM,Ruckerl D,Jenkins S,Ward LN,Kurtz ZD,et al. Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct[J]. Blood,2014,123(20):e110-e122.
[28] Laskin DL,Malaviya R,Laskin JD. Role of macrophages in acute lung injury and chronic fibrosis induced by pulmonary toxicants[J]. Science,2019,168(2):287-301.
[29] Martinez FO,Gordon S. The M1 and M2 paradigm of macrophage activation:time for reassessment[J/OL]. F1000Prime Rep,2014,6:13(2014-03-03).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944738/
[30]Groves AM,Johnston CJ,Misra RS,Wil iams JP,Finkelstein JN. Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation[J]. Int J Radiat Biol,2016,92(12):754-765.
[31] Pello OM,De Pizzol M,Mirolo M,Soucek L,Zammataro L,Amabile A,et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology[J]. Blood,2012,119(2):411-421.
[32] Chistiakov DA, Myasoedova VA, Revin VV,Orekhov AN,Bobryshev YV. The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2[J]. Immunobiology,2018,223(1):101-111.
[33] Sica A, Mantovani A. Macrophage plasticity and polarization:in vivo veritas[J]. J Clin Invest,2012,122(3):787-795.
[34] Yang G,Volk A,Petley T,Emmel E,Giles-Komar J,Shang X, et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness,inflammation and airway remodeling[J]. Cytokine,2004,28(6):224-232.
[35] Mora AL,Torres-González E,Rojas M,Corredor C,Ritzenthaler J,Xu J,et al. Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis[J]. Am J Respir Cell Mol Biol,2006,35(4):466-473.
[36] Murray PJ,Wynn TA. Protective and pathogenic functions of macrophage subsets[J]. Nat Rev Immunol,2011,11(11):723-737.
[37] Carneiro PJ,Clevelario AL,Padilha GA,Silva JD,Kitoko JZ,Olsen PC,et al. Bosutinib therapy ameliorates lung inflammation and fibrosis in experimental silicosis[J/OL]. Front Physiol,2017,8:159(2017-03-15). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350127/
[38] Misson P,van den Br?le S,Barbarin V,Lison D,Huaux F. Markers of macrophage differentiation in experimental silicosis[J]. J Leukoc Biol,2004,76(5):926-932.
[39] Weng SY,Padberg K,Wang XY,Kim YO,Crosby J,McCaleb M,et al. Regulation of liver fibrosis by tuning M2 macrophage polarization through IL-4Rαinhibition[J]. J Hepatol,2014,60(1):S279-S280.
[40] Lech M,Anders HJ. Macrophages and fibrosis:How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair[J]. Biochim Biophys Acta,2013,1832(7):989-997.
[41] Shamskhou EA, Kratochvil MJ, Orcholski ME,Nagy N,Kaber G,Steen E,et al. Hydrogel-based delivery of IL-10 improves treatment of bleomycininduced lung fibrosis in mice[J]. Biomaterials,2019,203:52-62.
[42] Sun L, Louie MC, Vannella KM, Wilke CA,LeVine AM,Moore BB,et al. New concepts of IL-10-induced lung fibrosis:fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis[J]. Am J Physiol Lung Cell Mol Physiol,2011,300(3):L341-L353.
[2] Woodcock HV,Molyneaux PL,Maher TM. Reducing lung function decline in patients with idiopathic pulmonary fibrosis:potential of nintedanib[J]. Drug Des Devel Ther,2013,7:503-510.
[3] Desai O,Winkler J,Minasyan M,Herzog EL. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis[J/OL]. Front Med(Lausanne),2018,5:43(2018-03-20). https://www. ncbi. nlm.nih.gov/pmc/articles/PMC5869935/
[4] Oeser K,Maxeiner J,Symowski C,Stassen M,Voehringer D. T cells are the critical source of IL-4/IL-13 in a mouse model of alergic asthma[J]. Alergy,2015,70(11):1440-1449.
[5] Ladjemi MZ,Gras D,Dupasquier S,Detry B,Lecocq M,Garulli C,et al. Bronchial epithelial IgA secretion is impaired in asthma. Role of IL-4/IL-13[J]. Am J Respir Crit Care Med,2018,197(11):1396-1409.
[6] Majumdar S1, Li D, Ansari T, Pantelidis P,Black CM,Gizycki M,et al. Different cytokine profiles in cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis:a quantitative study of open lung biopsies[J]. Eur Respir J,1999,14(2):251-257.
[7]Dong X. Effect of tranilast on IL-4,IL-13 expression and pulmonary fibrosis caused by paraquate poisoning in rats(曲尼司特在大鼠百草枯中毒肺纤维化过程中IL-4、IL-13的相关性研究)[D]. Zunyi:Zunyi Medical College(遵义医学院),2014.
[8]Chen C,Zhang X,Hong ZP. Research progress in key cells and molecules in pathogenesis of pulmonary fibrosis[J]. Basic Clin Med(基础医学与临床),2018,38(9):1329-1332.
[9] Zhu L,Fu X,Chen X,Han X,Dong P. M2 macrophages induce EMT through the TGF-β/Smad2 signaling pathway[J]. Cel Biol Int,2017,41(9):960-968.
[10] Li GS. Effect of cytokines and T regulatory cells in bleomycin-induced pulmonary fibrosis in rats(细胞因子及调节性T细胞在大鼠肺纤维化中的作用)[D].Taiyuan:Shanxi Medical University(山西医科大学),2007.
[11] Lauritzsen GF,Bogen B. Idiotype-specific,major histocompatibility complex restricted T cells are of both Th1 and Th2 type[J]. Scand J Immunol,1991,33(6):647-656.
[12] Szabo SJ,Jacobson NG,Dighe AS,Gubler U,Murphy KM. Developmental commitment to the Th2 lineage by extinction of IL-12 signaling[J]. Immunity,1995,2(6):665-675.
[13] Anthony RM,Kobayashi T,Wermeling F,Ravetch JV.Intravenous gammaglobulin suppresses inflammation through a novel Th2 pathway[J]. Nature,2011,475(7354):110-113.
[14] Palmer LD,Maloney KN,Boyd KL,Goleniewska AK,Toki S,Maxwel CN,et al. The innate immune protein S100A9 protects from Th2-mediated al ergic airway inflammation[J/OL]. Am J Respir Cell Mol Biol,2019(2019-04-03). https://www.atsjournals.org/doi/abs/10.1165/rcmb.201 8-0217OC
[15] Dong J, Ma Q. Type 2 immune mechanisms in carbon nanotube-induced lung fibrosis[J/OL]. Front Immunol,2018,9:1120(2018-05-22). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972321/
[16] Mojiri-Forushani H, Hemmati AA, Khodadadi A,Rashno M. Valsartan attenuates bleomycin-induced pulmonary fibrosis by inhibition of NF-κB expression and regulation of Th1/Th2 cytokines[J]. Immunopharmacol Immunotoxicol,2018,40(3):225-231.
[17] Singh B, Kasam RK, Sontake V, Wynn TA,Madala SK. Repetitive intradermal bleomycin injections evoke T-helper cel 2 cytokine-driven pulmonary fibrosis[J]. Am J Physiol Lung Cel Mol Physiol,2017,313(5):L796-L806.
[18] Wei Q,Sha Y,Bhattacharya A,Abdel Fattah E,Bonilla D,Jyothula SS,et al. Regulation of IL-4receptor signaling by STUB1 in lung inflammation[J].Am J Respir Crit Care Med,2014,189(1):16-29.
[19] Zhang C,Zhao H,Li BL,Fu-Gao,Liu H,Cai JM,et al. CpG-oligodeoxynucleotides may be effective for preventing ionizing radiation induced pulmonary fibrosis[J]. Toxicol Lett,2018,292:181-189.
[20] Grabarz F,Aguiar CF,Correa-Costa M,Braga TT,Hyane MI,Andrade-Oliveira V,et al. Protective role of NKT cel s and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis[J].Inflammopharmacology,2018,26(2):491-504.
[21] Arora S,Dev K,Agarwal B,Das P,Syed MA.Macrophages:their role,activation and polarization in pulmonary diseases[J]. Immunobiology,2018,223(4-5):383-396.
[22] Chávez-Galán L,Olleros ML,Vesin D,Garcia I.Much more than M1 and M2 macrophages,there are also CD169+and TCR+macrophages[J/OL].Front Immunol,2015,6:263(2015-05-26). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443739/
[23] Parisi L,Gini E,Baci D,Tremolati M,Fanuli M,Bassani B,et al. Macrophage polarization in chronic inflammatory diseases:killers or builders?[J/OL].J Immunol Res,2018,2018:8917804(2018-01-14).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821995/
[24] Kreider T,Anthony RM,Urban JF Jr,Gause WC.Alternatively activated macrophages in helminth infections[J]. Curr Opin Immunol,2007,19(4):448-453.
[25] Misharin AV,Morales-Nebreda L,Reyfman PA,Cuda CM,Walter JM,Mc Quattie-Pimentel AC,et al.Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span[J]. J Exp Med,2017,214(8):2387-2404.
[26] Baran CP,Opalek JM,Mc Maken S,Newland CA,O′Brien JM Jr,Hunter MG,et al. Important roles for macrophage colony-stimulating factor,CC chemokine ligand 2,and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis[J]. Am J Respir Crit Care Med,2007,176(1):78-89.
[27] Gundra UM,Girgis NM,Ruckerl D,Jenkins S,Ward LN,Kurtz ZD,et al. Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct[J]. Blood,2014,123(20):e110-e122.
[28] Laskin DL,Malaviya R,Laskin JD. Role of macrophages in acute lung injury and chronic fibrosis induced by pulmonary toxicants[J]. Science,2019,168(2):287-301.
[29] Martinez FO,Gordon S. The M1 and M2 paradigm of macrophage activation:time for reassessment[J/OL]. F1000Prime Rep,2014,6:13(2014-03-03).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944738/
[30]Groves AM,Johnston CJ,Misra RS,Wil iams JP,Finkelstein JN. Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation[J]. Int J Radiat Biol,2016,92(12):754-765.
[31] Pello OM,De Pizzol M,Mirolo M,Soucek L,Zammataro L,Amabile A,et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology[J]. Blood,2012,119(2):411-421.
[32] Chistiakov DA, Myasoedova VA, Revin VV,Orekhov AN,Bobryshev YV. The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2[J]. Immunobiology,2018,223(1):101-111.
[33] Sica A, Mantovani A. Macrophage plasticity and polarization:in vivo veritas[J]. J Clin Invest,2012,122(3):787-795.
[34] Yang G,Volk A,Petley T,Emmel E,Giles-Komar J,Shang X, et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness,inflammation and airway remodeling[J]. Cytokine,2004,28(6):224-232.
[35] Mora AL,Torres-González E,Rojas M,Corredor C,Ritzenthaler J,Xu J,et al. Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis[J]. Am J Respir Cell Mol Biol,2006,35(4):466-473.
[36] Murray PJ,Wynn TA. Protective and pathogenic functions of macrophage subsets[J]. Nat Rev Immunol,2011,11(11):723-737.
[37] Carneiro PJ,Clevelario AL,Padilha GA,Silva JD,Kitoko JZ,Olsen PC,et al. Bosutinib therapy ameliorates lung inflammation and fibrosis in experimental silicosis[J/OL]. Front Physiol,2017,8:159(2017-03-15). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350127/
[38] Misson P,van den Br?le S,Barbarin V,Lison D,Huaux F. Markers of macrophage differentiation in experimental silicosis[J]. J Leukoc Biol,2004,76(5):926-932.
[39] Weng SY,Padberg K,Wang XY,Kim YO,Crosby J,McCaleb M,et al. Regulation of liver fibrosis by tuning M2 macrophage polarization through IL-4Rαinhibition[J]. J Hepatol,2014,60(1):S279-S280.
[40] Lech M,Anders HJ. Macrophages and fibrosis:How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair[J]. Biochim Biophys Acta,2013,1832(7):989-997.
[41] Shamskhou EA, Kratochvil MJ, Orcholski ME,Nagy N,Kaber G,Steen E,et al. Hydrogel-based delivery of IL-10 improves treatment of bleomycininduced lung fibrosis in mice[J]. Biomaterials,2019,203:52-62.
[42] Sun L, Louie MC, Vannella KM, Wilke CA,LeVine AM,Moore BB,et al. New concepts of IL-10-induced lung fibrosis:fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis[J]. Am J Physiol Lung Cell Mol Physiol,2011,300(3):L341-L353.
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