Th17/IL-17水平在儿童哮喘发病中的变化及临床意义

目的探讨Th17细胞及IL-17水平在哮喘儿童外周血中水平的变化及其临床意义。方法选取35例轻度哮喘患儿、25例中重度哮喘患儿及30例健康儿童为研究对象,采用流式细胞术检测外周血Th17细胞百分率,采用酶联免疫吸附试验(ELISA)检测血清IL-17水平,观察两者变化及与哮喘严重程度的关系。结果中重度哮喘组患儿Th17细胞百分率明显高于健康对照组及轻度哮喘组,差异具有统计学意义(P0.01),轻度组与健康对照组之间差异无统计学意义(P0.05);血清IL-17水平在中重度哮喘组中明显高于轻度哮喘组和健康对照组,差异具有统计学意义(P均0.01),而在健康对照组与轻度哮喘组中,差异无统计学意义(P0.05);相关性分析结果显示,哮喘患儿外周血Th17细胞百分率与血清IL-17水平呈正相关(r=0.918,P0.05),外周血Th17细胞百分率均与哮喘严重程度呈正相关(r=0.867,P0.05);血清IL-17水平与哮喘严重程度也呈正相关(r=0.954,P0.05)。结论中重度支气管哮喘儿童外周血Th17细胞表达及IL-17水平增高,且与病情严重程度呈正相关。     

支气管哮喘急性发作期患者血清IL-17和转化生长因子β2的表达及其意义

目的 探讨支气管哮喘(简称哮喘)患者外周血IL-17和转化生长因子β2(TGF-β2)的表达及其意义.方法 将72例哮喘急性发作患者作为哮喘组,根据发作的严重程度分为3组,其中重度组20例、中度组28例、轻度组24例;18例健康者为对照组;应用ELISA法分别进行入组者外周血IL-17、TGF-β2检测;哮喘患者进行规范化梯度治疗3个月后复测IL-17、TGF-β2、肺功能,分析IL-17、TGF-β2与肺功能指标的相关性.结果 ①随着哮喘严重程度逐渐增加,患者外周血IL-17、TGF-β2浓度逐渐增加,FEV1％pred逐渐下降,差异均有统计学意义(F=37.794、27.557,P＜0.01);各组间IL-17、TGF-β2相互比较差异均有统计学意义(P＜0.01).②外周血IL-17、TGF-β2水平与患者年龄、BMI无相关性(P＞0.05);与FEV1％ pred呈负相关(r=-0.794、-0.468,P＜0.01);外周血IL-17与TGF-β2水平呈正相关(r=0.527,P＜0.01).③经规范化梯度治疗3个月后72例哮喘患者外周血IL-17、TGF-β2较前明显降低,FEV1％pred明显升高,较治疗前相比差异均有统计学意义(P＜0.01);但其IL-17、TGF β2水平仍高于对照组,FEV1％ pred低于对照组,差异均有统计学意义(P＜0.01).结论 哮喘患者外周血上升的TGF β2、IL-17和哮喘的发病密切相关,两者的表达水平呈正相关.TGF-β2、IL-17的测定对哮喘严重程度的判断、炎症水平及气道重建程度的评估具有一定的参考价值.     

哮喘急性发作FeNO与外周血嗜酸粒细胞及肺功能的相关性研究

目的探讨支气管哮喘急性发作期患者呼出气一氧化氮(FeNO)水平与疾病急性发作严重程度的相关性。方法选取我院86例门诊或住院哮喘急性发作期患者作为研究对象,并分为轻度组、中度组及重度组,采用瑞典奈尔斯(NIOX)一氧化氮测定仪检测FeNO数值,并选取同期34例健康体检者为对照组,所有研究对象均行外周血Eos计数、肺功能检测及呼出气一氧化氮水平检测,统计并分析相关数据。结果哮喘组(轻度组、中度组、重度组)与对照组FeNO测量值、外周血Eos计数、肺功能各项指标均存在明显差异,差异具有统计学意义(P0.05),随哮喘急性发作的严重程度增加,FeNO值明显增加,轻度组、中度组与重度组间差异具有显著性(P0.05);FeNO水平与外周血Eos均呈正相关(r=0.612,P0.05),但与肺功能各指标均无明显相关性。结论 FeNO可作为哮喘急性发作的评测指标,根据FeNO值的高低,可以一定程度评价哮喘发作的严重度。     

诱导痰气道炎症指标与支气管哮喘病情关系的探讨

目的 探讨气道炎症指标对支气管哮喘(简称哮喘)患者病情监测及治疗的意义.方法 收集2004年1月至2006年1月在北京大学第三医院呼吸科门诊就诊的近半年来未使用口服或吸入激素治疗的哮喘患者87例.进行哮喘症状评分、肺功能检查、诱导痰上清液检测白介素-8(IL-8)浓度及嗜酸粒细胞阳离子蛋白(ECP)浓度,对所有患者病情分级状况和气道炎症指标进行分析,探讨病情严重程度与气道炎症之间的关系;分析急性发作与气道炎症之间的关系.结果 (1)重度哮喘患者中性粒细胞、IL-8水平较轻中度患者明显增高;(2)急性发作期患者嗜酸性粒细胞(EOS)、ECP较缓解期明显增高;(3)中性粒细胞与第1秒用力呼气量(FEV1)呈负相关(r=-0.522,P＜0.05);中性粒细胞与IL-8呈正相关(r=0.832,P＜0.05);(4)ECP、EOS与FEV1、症状评分均无相关性(r=-0.209,r=-0.189,P均＞0.05;r=-0.289,r=-0.229,P均＞0.05);ECP与EOS呈正相关(r=0.852,P＜0.01);(5)中性粒细胞对重度哮喘的阳性预测值为91%,EOS对哮喘急性发作的阳性预测值为92.5%,ECP对哮喘急性发作的阳性预测值98.5%.结论 (1)中性粒细胞、IL-8与病情严重程度有关,重度哮喘患者中性粒细胞、IL-8明显增高;(2)ECP、EOS与哮喘的急性发作有关,急性发作期哮喘患者ECP、EOS明显增高;(3)气道炎症指标可用于监测哮喘病情和调整哮喘治疗.     

哮喘患儿呼出气一氧化氮浓度、肺功能及哮喘控制测试评分的相关性及其评估价值研究

目的探讨哮喘患儿呼出气一氧化氮(Fe NO)浓度、肺功能、哮喘控制测试(ACT)评分的相关性及其评估价值。方法选取2013年12月—2014年12月在衡水市桃城区妇幼保健院小儿呼吸科门诊初治1个月后的哮喘患儿162例,检测患儿Fe NO浓度及肺功能,进行ACT评分,并分析FeNO浓度、肺功能及ACT评分间的相关性。结果 162例患儿中肺功能正常者105例(占64.81%),肺功能轻度减退者57例(占35.19%);FeNO正常者64例(占39.51%),偏高者62例(占38.27%),较高者36例(占22.22%)。Pearson相关性分析结果显示,ACT评分与FeNO浓度呈中度负相关(r=-0.668,P=0.000);ACT评分与第一秒用力呼气容积占预计值百分比(FEV1%)呈高度正相关(r=0.754,P=0.000);FEV1%与FeNO浓度呈中度负相关(r=-0.524,P=0.000)。结论哮喘患儿FeNO、肺功能及ACT评分间具有相关性,ACT评分可用以评估哮喘患儿疾病控制情况,肺功能和FeNO浓度可用以评估哮喘患儿气道炎症和疾病控制情况。     

M1型和M2型巨噬细胞及相关组织因子在结核性胸膜炎患者治疗前后的变化及意义

目的在结核性胸膜炎(TP)中探讨M1、M2巨噬细胞及相关组织因子在抗TP治疗前后的表达变化和意义。方法使用流式细胞术检测TP患者与健康人群外周血及胸腔积液中单个核细胞(PBMC/PFMC)M1、M2巨噬细胞的表达率及TP患者经1个月规律抗TP治疗后PBMC与PFMC中M1、M2巨噬细胞的表达变化,ELISA检测外周血及胸腔积液中相关因子IL-10、IL-1、t-PA、PAI-1、ADA、LDH和蛋白的表达水平,分析健康人群与TP患者上述指标的表达差异和治疗后TP患者外周血及胸腔积液中上述指标的变化及各指标间的相关性。结果 TP患者PBMC中M2型巨噬细胞比例显著增加,且IL-10、PAI-1表达水平明显高于健康人群,而t-PA明显降低;在TP患者PFMC中M2型巨噬细胞比例显著高于M1型;TP患者中,外周血中M2型巨噬细胞表达与IL-10、PAI-1表达水平呈正相关,胸腔积液中M1型巨噬细胞与IL-12呈正相关,而M2型巨噬细胞与IL-10、PAI-1、ADA、LDH呈正相关,与t-PA呈明显负相关。治疗后,TP患者PBMC及PFMC中M1/M2极化现象得到明显改善,其中以M2型巨噬细胞比例减少最为显著。结论在TPPBMC与PFMC中均以M2巨噬细胞占主导地位,且外周血与PE中IL-10、PAI-1、t-PA与ADA、LDH水平与M2型巨噬细胞具有相关性,抗TP可明显改善M2巨噬细胞及相关细胞因子过度表达的现象。     

中性粒细胞-淋巴细胞比值与哮喘患者肺功能、急性发作关系研究

目的探讨外周血中性粒细胞-淋巴细胞比值(neutrophil-lymphocyte ratio, NLR)与哮喘患者肺功能及未来急性发作之间的关系。方法收集2016年9月-2017年5月在徐州医科大学附属医院确诊的成人支气管哮喘急性发作期患者204例。分别记录ACT评分,测定1秒钟用力呼气容积(FEV_1)、FEV_1占预计值百分比(FEV_1%)、用力肺活量(FVC)及FEV_1/FVC,检测血常规,记录未来一年中患者是否出现哮喘急性发作。根据NLR(NLR=中性粒细胞数绝对值/淋巴细胞数绝对值)四分位点将患者分为4组(Q1≤1.76,1.77Q2≤2.80,2.80Q3≤5.43,Q45.43),分别比较四组患者ACT评分、肺功能、未来一年出现哮喘急性发作的百分比。结果 Q1、Q2、Q3组患者FEV_1%和FEV_1/FVC差异无统计学意义(均P0.05)。Q4组的FEV_1%和FEV_1/FVC明显高于其余3组,且存在统计学意义(P0.05),FEV_1%、FEV_1/FVC与NLR均呈负性相关P0.01(r=-0.478、r=-0.4)。Logistics回归分析显示NLR、FEV_1%、过敏、使用ICS对哮喘未来急性发作有统计学意义,FEV_1%60%、使用ICS是哮喘未来急性发作的保护性因素,而NLR与过敏因素是则是哮喘未来急性发作的危险因素,ACT评分、吸烟与哮喘未来急性发作无统计学意义(P0.05)。结论哮喘患者NLR水平与气流受限呈负性相关,NLR是哮喘急性发作的独立危险因素。     

嗜碱性粒细胞活化状态对哮喘患儿急性发作次数的影响分析

目的探讨嗜碱性粒细胞活化状态对哮喘患儿急性发作次数的影响分析。方法选取2015年3月-2016年5月我院收治的哮喘急性发作期患儿57例,根据其病情严重程度分为:轻度组:轻度患者24例和中重度组:中重度患者33例。另选取同期健康体检儿童40例。采用流式细胞仪检测外周血嗜碱性粒细胞中CD63、CD203c水平和化学发光免疫分析法检测血清总Ig E水平。观察哮喘患儿经治疗临床症状及体征缓解后,随访追踪12个月,记录随访期内哮喘患儿急性发作次数和严重程度。结果哮喘患儿急性发作期血清总Ig E水平高于缓解期和健康儿童,差异有统计学意义(P0.05);哮喘轻度患儿CD63、CD203c水平与中重度患儿相比,无显著性差异(P0.05);每年发病超过5次的哮喘患儿CD63、CD203c水平均较每年发病不足5次的哮喘患儿高,差异有统计学意义(P0.001);在随访12个月内,血清IgE、CD63、CD203c水平越高,急性发作次数越多,呈正相关(r=0.513,r=1.17,r=0.876,P0.05)。结论哮喘患儿急性发作期血清总IgE、CD63、CD203c水平上升,与其预后密切相关:血清IgE、CD63、CD203c水平越高,患儿急性发作次数越多,与病情严重程度无关。     

哮喘患儿治疗前后血清不同促炎因子和抗炎因子水平改变的临床意义研究

目的探讨哮喘患儿治疗前后血清不同促炎因子和抗炎因子水平改变的临床意义。方法连续性收录80例哮喘急性发作患儿,综合分析比较治疗前后血清促炎因子(IFNγ,TNFα,IL-1β以及Il-6)和抗炎因子(IL-10,TGFβ以及IL-4)水平改变。结果哮喘患儿治疗前血清IFNγ,TNFα以及IL-6等促炎因子水平高于对照组(P0.05)。经治疗后,血清IFNγ和Il-6水平下降最为明显(P0.05)。哮喘患儿治疗前血清IL-10和IL-4等抗炎因子水平低于对照组(P0.05)。经治疗后,血清IL-10和IL-4水平上升最为明显(P0.05)。危重亚组患儿血清IFNγ和IL-6水平明显高于轻度亚组(P0.05)。哮喘分级和促炎因子TNFα呈负相关(r=-0.589,P0.05)。促炎因子TNFα与IL-6(r=0.599,P0.05),IL-1β与IL-6(r=0.532,P0.05)之间存在正相关。促炎因子TNFα与抗炎因子TGFβ呈负相关(r=-0.662,P0.05)。结论哮喘患儿血清IFNγ、IL-6、IL-10和IL-4水平在治疗过程中动态变化,与哮喘严重程度密切相关。     

支气管哮喘儿童外周血神经生长因子水平变化及临床意义

目的研究支气管哮喘患儿血清神经生长因子水平及临床意义。方法研究分两组,研究组72例患支气管哮喘儿童,对照组80例无喘息发作支气管肺炎患儿,抽取患儿外周血,检测其血清神经生长因子水平。结果支气管哮喘组患儿外周血神经生长因子浓度为92.6±32.5 pg/ml,轻度、中度、重度哮喘临床发作患儿血神经生长因子浓度分别为53.2±18.5 pg/ml、97.8±22.7 pg/ml、162.4±28.6 pg/ml,血清NGF水平与临床发作程度呈正相关(r=0.62;P0.05)。对照组支气管肺炎患儿外周血NGF浓度为32.8±12.6 pg/ml,低于支气管哮喘儿童外周血神经生长因子水平(P0.001)。结论支气管哮喘儿童外周血NGF明显升高,并与临床发作程度正相关。     

Modulation of macrophage phenotype by cell shape

Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Although much is known about how soluble factors influence macrophage polarization, relatively little is known about how physical cues present in the extracellular environment might modulate proinflammatory (M1) vs. prohealing (M2) activation. Specifically, the role of cell shape has not been explored, even though it has been observed that macrophages adopt different geometries in vivo. We and others observed that macrophages polarized toward different phenotypes in vitro exhibit dramatic changes in cell shape: M2 cells exhibit an elongated shape compared with M1 cells. Using a micropatterning approach to control macrophage cell shape directly, we demonstrate here that elongation itself, without exogenous cytokines, leads to the expression of M2 phenotype markers and reduces the secretion of inflammatory cytokines. Moreover, elongation enhances the effects of M2-inducing cytokines IL-4 and IL-13 and protects cells from M1-inducing stimuli LPS and IFN-γ. In addition shape- but not cytokine-induced polarization is abrogated when actin and actin/myosin contractility are inhibited by pharmacological agents, suggesting a role for the cytoskeleton in the control of macrophage polarization by cell geometry. Our studies demonstrate that alterations in cell shape associated with changes in ECM architecture may provide integral cues to modulate macrophage phenotype polarization.Macrophages play an essential role in innate immunity and are involved in a variety of immune functions, including host defense and wound healing. In addition, these cells participate in the progression of many chronic inflammatory diseases. To fulfill their functionally distinct roles, macrophages are capable of polarizing toward a spectrum of phenotypes, which include classical (proinflammatory, M1) and alternative (anti-inflammatory, prohealing, M2) activation states, as well as a regulatory phenotype and subtypes of these broad classifications (1). In the presence of inflammatory stimuli and danger signals, macrophages polarize toward the M1 state and release reactive species and inflammatory cytokines to fight pathogens. In contrast, a wound healing environment promotes polarization toward an M2 phenotype and leads to cellular processes that facilitate tissue repair. Although distinct macrophage subpopulations are clearly observed at different phases of the immune response to infection and injury (2), regulation of phenotypic polarization of these remarkably plastic cells still remains poorly defined.Activated macrophages are derived from circulating monocytes or resident tissue macrophages and migrate through the extracellular space in response to chemotactic agents to reach the target wound or infection site. Although it is thought that cytokines and chemokines are the primary regulators of macrophage behavior (3), some recent studies suggest that tissue structure and physical cues in the extracellular environment also contribute to their function (4). In the context of tissue healing, deposition of the provisional ECM and collagen remodeling may indeed influence macrophage polarization. In support of this, different macrophage subpopulations in vivo have been shown to exist within specific tissue architectures. For example, during atherosclerosis, although both M1 and M2 phenotypes are present, M2 cells dominate within the collagen-rich fibrous cap and adventitia surrounding the plaque and exhibit an elongated morphology (5, 6). Furthermore, it was recently shown using intravital imaging that macrophages align and migrate along collagen fibrils within a tumor (7). Despite evidence suggesting that macrophages adopt different geometries in vivo, how these changes in cell shape might feed back to regulate their functional phenotype has not been previously explored.Cell shape changes have been associated with different functional states of cells (8), including proliferation and apoptosis (9), nuclear organization (10), stem cell differentiation (11, 12), and muscle cell contractility (13). It is thought that interactions between the ECM, cell surface adhesion proteins, and cytoskeleton, as well as subsequent changes in intracellular contractility, are important in mediating shape-induced effects (14). Although these molecular structures are known to be key mediators of mechanotransduction in many cell types, their roles in sensing physical cues in the macrophage microenvironment and regulating macrophage polarization state are not known.Here, we investigate the role of cell elongation, which is observed in cells within fibrous tissue architectures, on the polarization of macrophages. We observed that macrophages exhibit different degrees of elongation when stimulated toward M1 or M2 phenotypes with cytokines in vitro. Using a micropatterning approach to control the shape of cells directly, we found that elongation of cells induced polarization toward an M2 phenotype. Moreover, elongation enhanced the effect of M2-inducing cytokines and inhibited the effect of M1-inducing cytokines, suggesting that cell shape plays an important role in modulation of the phenotypic polarization of macrophages. Transduction of cell shape to changes in macrophage phenotype was dependent on contractility within the actin cytoskeleton, because pharmacological inhibition of actin or myosin prevented polarization by cell shape. Shape-induced cell polarization may play a critical role in modulation of macrophage phenotype by means of changes in ECM structure during wound healing and tissue repair.     

Sequential Co-infection of Heligmosomoides polygyrus and Mycobacterium tuberculosis Determine Lung Macrophage Polarization and Histopathological Changes

BackgroundTuberculosis is a chronic infection caused by Mycobacterium tuberculosis (M.tb), which needs proper macrophage activation for control. It has been debated whether the co-infection with helminth will affect the immune response to mycobacterial infection.ObjectiveTo determine the effect of sequential co-infection of Heligmosomoides polygyrus (H.pg) nematodes and M.tb on T cell responses, macrophages polarization and lung histopathological changes.MethodThis study used 49 mice divided into 7 treatment groups, with different sequence of infection of M.tb via inhalation and H.pg via oral ingestion for 8 and 16 weeks. T cells response in the lung, intestine, and peripheral blood were determined by flow cytometry. Cytokines (IL-4, IFN-γ, TGB-β1, and IL-10) were measured in peripheral blood using ELISA. Lung macrophage polarization were determined by the expression of iNOS (M1) or Arginase 1 (M2). Mycobacterial count were done in lung tissue. Lung histopathology were measured using Dorman’s semiquantitative score assessing peribronchiolitis, perivasculitis, alveolitis, and granuloma formation.ResultM.tb infection induced Th1 response and M1 macrophage polarization, while H.pg infection induced Th2 and M2 polarization. In sequential co-infection, the final polarization of macrophage was dictated by the sequence of co-infection. However, all groups with M.tb infection showed the same degree of mycobacterial count in lung tissues and lung tissue histopathological changes.ConclusionSequential co-infection of H.pg and M.tb induces different T cell response which leads to different macrophage polarization in lung tissue. Helminth infection induced M2 lung macrophage polarization, but did not cause different mycobacterial count nor lung histopathological changes.     

巨噬细胞在支气管哮喘中的作用及研究进展

受微环境变化的影响,巨噬细胞分为经典激活的巨噬细胞(M1)和非经典激活的巨噬细胞(M2).M1型巨噬细胞可释放如肿瘤坏死因子α(TNF-α)和IL-1β等促炎因子加重炎症反应,也可因极化的增多发挥抗炎作用.M2型巨噬细胞分为M2a、M2b和M2c 3种亚型,M2a及M2b型巨噬细胞主要产生炎性细胞因子如ID4和IL-13,M2c型巨噬细胞主要产生抗炎细胞因子如IL-10并有很强的吞噬功能.细胞因子、趋化因子和免疫调节细胞影响着M1型和M2型巨噬细胞的平衡.巨噬细胞不同的极化在支气管哮喘发生与发展中起到重要的作用.     

原发性胆汁性肝硬化患者外周血单核巨噬细胞中Notch受体表达情况

目的探讨原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)患者外周血中巨噬细胞膜Notch受体表达情况及其与巨噬细胞极化的关系。方法随机抽取上海中医药大学附属曙光医院收治的确诊为PBC患者30例和健康体检者15名,分为早期PBC组、晚期PBC组和健康对照组,采集空腹血,流式细胞术法检测外周血M1和M2型巨噬细胞及膜表面Notch受体表达水平。结果早期PBC患者巨噬细胞膜表面Notch1受体表达较对照组高(P<0.05),而Notch2受体和Notch3受体表达水平与健康对照组比较,差异无统计学意义(P>0.05);晚期PBC患者巨噬细胞膜表面Notch1和Notch3受体表达较对照组高(P<0.05),但Notch2受体表达差异无统计学意义(P>0.05)。晚期PBC患者Notch1受体和Notch3受体表达水平较早期PBC患者高(P<0.05)。巨噬细胞极化M2/M1比值与Notch受体表达水平呈线性相关。结论PBC患者外周血巨噬细胞膜表面Notch受体表达异常,且与巨噬细胞极化呈直线相关。     

Lipid Droplet Protein PLIN1 Regulates Inflammatory Polarity in Human Macrophages and is Involved in Atherosclerotic Plaque Development by Promoting Stable Lipid Storage

Aim: Perilipins (PLINs), peripheral lipid droplet (LD) proteins, play important roles in lipid accumulation and maturation in adipocytes. The relationship between PLIN family proteins and macrophage polarization in atherosclerosis has not been elucidated. Methods: The experiments used tissues from human arteries of 65 patients who had undergone a carotid endarterectomy, and cultured macrophages generated from healthy human peripheral blood mononuclear cells. Results: Plaque immunohistochemistry demonstrated co-expression of PLIN1 and PLIN2 in both symptomatic (n=31) and asymptomatic patients (n=34). PLIN2 mRNA expression increased 3.38-fold in the symptomatic group compared with those from asymptomatic. PLIN1 was not expressed on small LDs at a shorter incubation but was on large LDs at longer incubation with oxidized LDL and VLDL, while PLIN2 was observed after 24 h and increased with a longer incubation in cultured M1 macrophage. In M2 macrophages, PLIN1 was seen as early as 24 h following incubation with VLDL, and LD size increased with longer incubation. PLIN1 overexpression increased the size of LDs in M1 macrophages, even after a short incubation, and reduced the RNA expression ofTNFA,MMP2,ABCA1, andABCG1 versus the M1 control. Conversely, silencing of PLIN1 in M2 macrophages had the opposite effects on LD size and RNA expression. Conclusion: There was a relationship between macrophage polarity, cytosolic LD size, and PLIN1/PLIN2 expression levels. PLIN2 was mainly expressed in arterial plaques in symptomatic stroke patients, and associated with the inflammatory phenotype of human macrophages, while PLIN1 expression is closely associated with plaque stability and the anti-inflammatory phenotype.     

Interactions of helminths with macrophages: therapeutic potential for inflammatory intestinal disease

ABSTRACT

Introduction: Macrophages represent a highly heterogeneous and plastic cell type found in most tissues of the body; the intestine is home to enormous numbers of these cells. Considerable interest surrounds the ‘M2 macrophage,’ as it is able to control and regulate inflammation, while promoting tissue repair.

Areas covered: As potent inducers of M2 macrophages, intestinal helminths and helminth-derived products are ideal candidates for small molecule drug design to drive M2 macrophage polarization. Several gastrointestinal helminths have been found to cause M2 macrophage-inducing infections. This review covers current knowledge of helminth products and their impact on macrophage polarization, which may in the future lead to new therapeutic strategies.

A literature search was performed using the following search terms in PubMed: M2 macrophage, alternative activation, helminth products, helminth ES, helminth therapy, nanoparticle, intestinal macrophages. Other studies were selected by using references from articles identified through our original literature search.

Expert commentary: While the immunomodulatory potential of helminth products is well established, we have yet to fully characterize many components of the intestinal helminth product library. Current work aims to identify the protein motifs responsible for modulation of macrophages and other components of the immune system.     

弓形虫感染对THP-1巨噬细胞极化影响的研究

目的 探讨弓形虫感染对体外诱导的人外周血单核细胞(Human acute monocytic leukemia cell line,THP-1)极化特点的影响。方法 用佛波酯(PMA)诱导THP-148 h使之由悬浮的单核细胞诱导为贴壁的巨噬细胞,体外选择不同时间点感染弓形虫,用Diff染色分析弓形虫在细胞内的增殖情况。Western blot检测极化相关蛋白,Q-PCR检测mRNA的表达情况。结果 成功诱导得到贴壁的巨噬细胞模型,感染弓形虫后,M1型巨噬细胞标志性蛋白iNOS 及M2型巨噬细胞标志型蛋白Arg-1 36 h表达量与对照组差异明显(t=10.23,P<0.05)。Q-PCR的结果显示不同的处理组IL-1、IL-12、iNOS和TNF-α逐渐减少,而IL-10、Arg-1呈逐渐增加,到36 h达到顶峰(t=9.587,P<0.05)。结论 弓形虫RH株感染THP-1巨噬细胞后可以在胞内生长增殖,THP-1细胞感染后向M2型巨噬细胞方向极化。     

Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers

M-CSF favors the generation of folate receptor β-positive (FRβ?), IL-10-producing, immunosuppressive, M2-polarized macrophages [M2 (M-CSF)], whereas GM-CSF promotes a proinflammatory, M1-polarized phenotype [M1 (GM-CSF)]. In the present study, we found that activin A was preferentially released by M1 (GM-CSF) macrophages, impaired the acquisition of FRβ and other M2 (M-CSF)-specific markers, down-modulated the LPS-induced release of IL-10, and mediated the tumor cell growth-inhibitory activity of M1 (GM-CSF) macrophages, in which Smad2/3 is constitutively phosphorylated. The contribution of activin A to M1 (GM-CSF) macrophage polarization was evidenced by the capacity of a blocking anti-activin A antibody to reduce M1 (GM-CSF) polarization markers expression while enhancing FRβ and other M2 (M-CSF) markers mRNA levels. Moreover, an inhibitor of activin receptor-like kinase 4/5/7 (ALK4/5/7 or SB431542) promoted M2 (M-CSF) marker expression but limited the acquisition of M1 (GM-CSF) polarization markers, suggesting a role for Smad2/3 activation in macrophage polarization. In agreement with these results, expression of activin A and M2 (M-CSF)-specific markers was oppositely regulated by tumor ascites. Therefore, activin A contributes to the proinflammatory macrophage polarization triggered by GM-CSF and limits the acquisition of the anti-inflammatory phenotype in a Smad2-dependent manner. Our results demonstrate that activin A-initiated Smad signaling skews macrophage polarization toward the acquisition of a proinflammatory phenotype.     

Hepcidin Induces M1 Macrophage Polarization in Monocytes or THP-1 Derived Macrophages

Background: Macrophage polarization plays a critical role in determining the inflammatory states. Hepcidin is a key negative regulator of iron homeostasis and functions. Although hepcidin has been shown to affect ferroportin expression in macrophages, whether it affects macrophage polarization is still largely unknown. Objective: To address whether hepcidin induces macrophage polarization. Methods: The expression of iNOS and CD206, and the ratio of IFN-γ vs IL-4 in THP-1 derived macrophages upon hepcidin stimulation were evaluated. Further detected was the percentage of CD16+ M1, CD23+ M1, CD10+ M2 and CCL22+ M2 cells in monocyte derived macrophages. Results: M1 associated molecules were increased in hepcidin-treated cells, yet M2 associated molecules were increased when hepcidin was neutralized. Concomitantly, we observed a significant increase in IRF3 phosphorylation in hepcidin-stimulated cells. However, STAT6 phosphorylation with hepcidin was neutralized. Conclusion: Hepcidin is able to induce macrophage polarization towards M1 type, and might be utilized as a potential M1 macrophage agonist in clinical practice.