巨噬细胞M1/M2极化的信号通路研究进展
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摘要
巨噬细胞具高度可塑性、炎症因子诱导下分化异常等特点。在不同环境的刺激下巨噬细胞可极化为经典活化巨噬细胞(M1型巨噬细胞)和替代性活化巨噬细胞(M2型巨噬细胞),两者极化功能几乎相互拮抗。巨噬细胞的极化是一个多因子相互作用的复杂过程,受到多种信号分子及其通路的调控。本文将总结迄今为止研究较为成熟的JAK/STAT、PI3K/Akt、C-Jun N-terminal kinase(JNK)、Notch以及B7-H3/STAT3 5种信号通路。巨噬细胞是全身代谢、造血功能、血管生成、细胞凋亡以及肿瘤形成过程中的重要调节者,对巨噬细胞极化信号通路的研究可为巨噬细胞参与的相关疾病的治疗提供新的思路。
Plasticity and inflammatory factor-induced heterogeneity are main characteristics of macrophages.Thus, different environment-derived stimuli could induce the macrophage phenotypic polarization, such as classically activated macrophage(M1) and alternatively activated macrophage(M2). And the functions of the two kinds of polarization states are almost antistatic on each other. Macrophage polarization is a complex process, in which more than one factor interact on each other and regulated by a variety of signal molecules and signaling pathways. Here in this review, we show five signaling pathways which have been studied maturely until now, such as JAK/STAT, PI3K/Akt, C-Jun N-terminal kinase(JNK), Notch and B7-H3/STAT3 signaling pathway. Macrophages are the important regulators of the body metabolism, hematopoietic function, angiogenesis, apoptosis and the process of tumor formation. The review on signaling pathways of macrophage polarization may provide a new thought to treat macrophage-associated illnesses.
Plasticity and inflammatory factor-induced heterogeneity are main characteristics of macrophages.Thus, different environment-derived stimuli could induce the macrophage phenotypic polarization, such as classically activated macrophage(M1) and alternatively activated macrophage(M2). And the functions of the two kinds of polarization states are almost antistatic on each other. Macrophage polarization is a complex process, in which more than one factor interact on each other and regulated by a variety of signal molecules and signaling pathways. Here in this review, we show five signaling pathways which have been studied maturely until now, such as JAK/STAT, PI3K/Akt, C-Jun N-terminal kinase(JNK), Notch and B7-H3/STAT3 signaling pathway. Macrophages are the important regulators of the body metabolism, hematopoietic function, angiogenesis, apoptosis and the process of tumor formation. The review on signaling pathways of macrophage polarization may provide a new thought to treat macrophage-associated illnesses.
引文
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[20]Kono Y,Kawakami S,Higuchi Y,et al.In vitro evaluation of inhibitory effect of nuclear factor-kappa B activity by small interfering RNA on pro-tumor characteristics of M2-like macrophages[J].Biol Pharm Bull,2014,37(1):137-144.
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[22]Duvel K,Yecies JL,Menon S,et al.Activation of a metabolic gene regulatory network downstream of m TOR complex 1[J].Mol Cell,2010,39(2):171-183.
[23]Zhu YP,Brown JR,Sag D,et al.Adenosine 5′-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages[J].J Immunol(Baltimore,Md:1950),2015,194(2):584-594.
[24]Wei Y,Nazari Jahantigh M,Chan L,et al.The micro RNA-342-5p fosters inflammatory macrophage activation through an Akt1-and micro RNA-155-dependent pathway during atherosclerosis[J].Circulation,2013,127(15):1609-1619.
[25]Rocher C,Singla DK.SMAD-PI3K-Akt-m TOR pathway mediates BMP-7 polarization of monocytes into M2macrophages[J].PLo S One,2013,8(12):e84009.
[26]Pal M,Wunderlich CM,Spohn G,et al.Alteration of JNK-1 signaling in skeletal muscle fails to affect glucose homeostasis and obesity-associated insulin resistance in mice[J].PLo S One,2013,8(1):e54247.
[27]Han MS,Jung DY,Morel C,et al.JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation[J].Science,2013,339(6116):218-222.
[28]Gadang V,Kohli R,Myronovych A,et al.MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet[J].Am J Physiol Endocrinol Metab,2013,305(4):E549-556.
[29]Date D,Das R,Narla G,et al.Kruppel-like transcription factor 6 regulates inflammatory macrophage polarization[J].J Biol Chem,2014,289(15):10318-10329.
[30]Wang Z,Li Y,Kong D,et al.Cross-talk between mi RNA and Notch signaling pathways in tumor development and progression[J].Cancer Lett,2010,292(2):141-148.
[31]Xu H,Zhu J,Smith S,et al.Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization[J].Nat Immunol,2012,13(7):642-650.
[32]Sun TW,Gao Q,Qiu SJ,et al.B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence[J].Cancer Immunology,immunotherapy:CII,2012,61(11):2171-2182.
[33]Kang FB,Wang L,Li D,et al.Hepatocellular carcinomas promote tumor-associated macrophage M2-polarization via increased B7-H3 expression[J].Oncol Rep,2015,33(1):274-282.
[34]Sun J,Mao Y,Zhang YQ,et al.Clinical significance of the induction of macrophage differentiation by the costimulatory molecule B7-H3 in human non-small cell lung cancer[J].Oncol Lett,2013,6(5):1253-1260.
[35]Zhou D,Huang C,Lin Z,et al.Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways[J].Cell Signal,2014,26(2):192-197.
[2]Konttinen YT,Pajarinen J,Takakubo Y,et al.Macrophage polarization and activation in response to implant debris:influence by“particle disease”and“ion disease”[J].J Long Term Eff Med Implants,2014,24(4):267-281.
[3]Tomar S,Zumbrun E,Nagarkatti M,et al.Protective role of cannabinoid receptor 2 activation in galactosamine/lipopolysaccharide-induced acute liver failure through regulation of macrophage polarization and micro RNAs[J].J Pharmacol Exp Ther,2015,353(2):369-379.
[4]Kim YK,Oh SY,Jeon SG,et al.Airway exposure levels of lipopolysaccharide determine type 1 versus type 2experimental asthma[J].J Immunol(Baltimore,Md:1950),2007,178(8):5375-5382.
[5]Ceeraz S,Nowak EC,Noelle RJ.B7 family checkpoint regulators in immune regulation and disease[J].Trends Immunol,2013,34(11):556-563.
[6]Moreira AP,Cavassani KA,Hullinger R,et al.Serum amyloid P attenuates M2 macrophage activation and protects against fungal spore-induced allergic airway disease[J].J Allergy Clin Immunol,2010,126(4):712-721e717.
[7]Hall CJ,Boyle RH,Astin JW,et al.Immunoresponsive gene 1 augments bactericidal activity of macrophagelineage cells by regulating beta-oxidation-dependent mitochondrial ROS production[J].Cell Metabol,2013,18(2):265-278.
[8]Murray PJ.The JAK-STAT signaling pathway:input and output integration[J].J Immunol(Baltimore,Md:1950),2007,178(5):2623-2629.
[9]Hu JC,Brookings W,Aldridge MC.A case of solid pseudopapillary tumour of the pancreas and malignant mesothelioma[J].J Gastrointest Cancer,2007,38(2-4):71-73.
[10]Lawrence T,Natoli G.Transcriptional regulation of macrophage polarization:enabling diversity with identity[J].Nat Rev Immunol,2011,11(11):750-761.
[11]Szanto A,Balint BL,Nagy ZS,et al.STAT6 transcription factor is a facilitator of the nuclear receptor PPARgammaregulated gene expression in macrophages and dendritic cells[J].Immunity,2010,33(5):699-712.
[12]Park SJ,Lee KP,Kang S,et al.Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2macrophage polarization through IL-4[J].Cell Signal,2014,26(10):2249-2258.
[13]赵娜.巨噬细胞选择性活化的信号通路及其干预措施的研究进展[J].微生物学免疫学进展,2012,40(6):73-77.
[14]Silva A,Yunes JA,Cardoso BA,et al.PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability[J].J Clin Invest,2008,118(11):3762-3774.
[15]Maroulakou IG,Oemler W,Naber SP,et al.Akt1 ablation inhibits,whereas Akt2 ablation accelerates,the development of mammary adenocarcinomas in mouse mammary tumor virus(MMTV)-Erb B2/neu and MMTVpolyoma middle T transgenic mice[J].Cancer Res,2007,67(1):167-177.
[16]Green BD,Jabbour AM,Sandow JJ,et al.Akt1 is the principal Akt isoform regulating apoptosis in limiting cytokine concentrations[J].Cell Death Differ,2013,20(10):1341-1349.
[17]Xu F,Kang Y,Zhang H,et al.Akt1-mediated regulation of macrophage polarization in a murine model of Staphylococcus aureus pulmonary infection[J].J Infect Dis,2013,208(3):528-538.
[18]Arranz A,Doxaki C,Vergadi E,et al.Akt1 and Akt2protein kinases differentially contribute to macrophage polarization[J].Proc Nat Acad Scie USA,2012,109(24):9517-9522.
[19]Banerjee S,Cui H,Xie N,et al.mi R-125a-5p regulates differential activation of macrophages and inflammation[J].J Biol Chem,2013,288(49):35428-35436.
[20]Kono Y,Kawakami S,Higuchi Y,et al.In vitro evaluation of inhibitory effect of nuclear factor-kappa B activity by small interfering RNA on pro-tumor characteristics of M2-like macrophages[J].Biol Pharm Bull,2014,37(1):137-144.
[21]Hah YS,Cheon YH,Lim HS,et al.Myeloid deletion of SIRT1 aggravates serum transfer arthritis in mice via nuclear factor-kappa B activation[J].PLo S One,2014,9(2):e87733.
[22]Duvel K,Yecies JL,Menon S,et al.Activation of a metabolic gene regulatory network downstream of m TOR complex 1[J].Mol Cell,2010,39(2):171-183.
[23]Zhu YP,Brown JR,Sag D,et al.Adenosine 5′-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages[J].J Immunol(Baltimore,Md:1950),2015,194(2):584-594.
[24]Wei Y,Nazari Jahantigh M,Chan L,et al.The micro RNA-342-5p fosters inflammatory macrophage activation through an Akt1-and micro RNA-155-dependent pathway during atherosclerosis[J].Circulation,2013,127(15):1609-1619.
[25]Rocher C,Singla DK.SMAD-PI3K-Akt-m TOR pathway mediates BMP-7 polarization of monocytes into M2macrophages[J].PLo S One,2013,8(12):e84009.
[26]Pal M,Wunderlich CM,Spohn G,et al.Alteration of JNK-1 signaling in skeletal muscle fails to affect glucose homeostasis and obesity-associated insulin resistance in mice[J].PLo S One,2013,8(1):e54247.
[27]Han MS,Jung DY,Morel C,et al.JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation[J].Science,2013,339(6116):218-222.
[28]Gadang V,Kohli R,Myronovych A,et al.MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet[J].Am J Physiol Endocrinol Metab,2013,305(4):E549-556.
[29]Date D,Das R,Narla G,et al.Kruppel-like transcription factor 6 regulates inflammatory macrophage polarization[J].J Biol Chem,2014,289(15):10318-10329.
[30]Wang Z,Li Y,Kong D,et al.Cross-talk between mi RNA and Notch signaling pathways in tumor development and progression[J].Cancer Lett,2010,292(2):141-148.
[31]Xu H,Zhu J,Smith S,et al.Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization[J].Nat Immunol,2012,13(7):642-650.
[32]Sun TW,Gao Q,Qiu SJ,et al.B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence[J].Cancer Immunology,immunotherapy:CII,2012,61(11):2171-2182.
[33]Kang FB,Wang L,Li D,et al.Hepatocellular carcinomas promote tumor-associated macrophage M2-polarization via increased B7-H3 expression[J].Oncol Rep,2015,33(1):274-282.
[34]Sun J,Mao Y,Zhang YQ,et al.Clinical significance of the induction of macrophage differentiation by the costimulatory molecule B7-H3 in human non-small cell lung cancer[J].Oncol Lett,2013,6(5):1253-1260.
[35]Zhou D,Huang C,Lin Z,et al.Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways[J].Cell Signal,2014,26(2):192-197.