Azithromycin Reduces Exaggerated Cytokine Production by M1 Alveolar Macrophages in Cystic Fibrosis
Azithromycin Reduces Exaggerated Cytokine Production by M1 Alveolar Macrophages in Cystic Fibrosis
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DOI：
10.1165/rcmb.2008-0155oc
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发表时间：
2009-11-01
影响因子：
6.4
通讯作者：
Leal, Teresinha
中科院分区：
文献类型：
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作者：
Meyer, Magali;Huaux, Francois;Leal, Teresinha
巨噬细胞吞噬病原微生物，并通过产生多种炎症介质来协调免疫反应。据报道，囊性纤维化（CF）跨膜电导调节剂氯离子通道对巨噬细胞功能至关重要。巨噬细胞在CF中的确切表型和作用仍然未知。在F508 del突变纯合子的CIF小鼠和野生型对照动物中监测肺泡和腹膜巨噬细胞。研究了经典（M1）和替代（M2）巨噬细胞极化和对铜绿假单胞菌LIPS的反应，并在两种细胞群中检查了阿奇霉素的作用。我们发现，肺泡巨噬细胞计数是1.7倍高，CIF与野生型小鼠相比。巨噬细胞相关的趋化因子，趋化因子C-C基序配体（CCL）-2，被发现在突变小鼠的肺泡腔中至少丰富10倍。CIF小鼠腹腔内细胞计数和CCL-2蛋白水平也增加。与对照动物相比，F508 del-CF小鼠肺泡和腹膜细胞中M1和M2巨噬细胞极化均显著增强。在CIF巨噬细胞中，LPS刺激的促炎介质（如一氧化氮合酶-2，IL-1 β和CCL-2）表达增加，而抗炎IL-10表达减少。以1 mg/L加入细胞培养物中的阿奇霉素显著降低了M1诱导的CF和野生型肺泡巨噬细胞中促炎细胞因子（IL-1 β、CCL-2、TNF-α）的表达。我们的研究结果表明，CF巨噬细胞是无处不在的积累，这些细胞被极化向经典和替代激活状态。阿奇霉素通过M1极化CIF肺泡巨噬细胞下调炎性细胞因子的产生。
Macrophages phagocyte pathogenic microorganisms and orchestrate immune responses by producing a variety of inflammatory mediators. The cystic fibrosis (CF) transmembrane conductance regulator chloride channel has been reported to be of pivotal importance for macrophage functions. The exact phenotype and role of macrophages in CF is still unknown. Alveolar and peritoneal macrophages were monitored in CIF mice homozygous for the F508 del mutation and in wild-type control animals. Classical (M1) and alternative (M2) macrophage polarization and responses to LIPS from Pseudomonas aeruginosa were investigated, and the effect of azithromycin was examined in both cell populations. We show that alveolar macrophage counts were 1.7-fold higher in CIF as compared with wild-type mice. The macrophage-related chemokine, chemokine C-C motif ligand (CCL)-2, was found to be at least 10-fold more abundant in the alveolar space of mutant mice. Cell count and CCL-2 protein levels were also increased in the peritoneal cavity of CIF mice. Both M1 and M2 macrophage polarization were significantly enhanced in alveolar and peritoneal cells from F508del-CF mice as compared with control animals. LPS-stimulated expression of proinflammatory mediators, such as nitric oxide synthase-2, IL-1 beta, and CCL-2, was increased, whereas anti-inflammatory IL-10 expression was decreased in CIF macrophages. Azithromycin, added to cell cultures at 1 mg/liter, significantly reduced proinflammatory cytokine expression (IL-1 beta, CCL-2, TNF-alpha) in M1-induced CF and wild-type alveolar macrophages. Our findings indicate that CF macrophages are ubiquitously accumulated, and that these cells are polarized toward classical and alternative activation status. Azithromycin down-regulates inflammatory cytokine production by M1-polarized CIF alveolar macrophages.