Benmoussa Khaddouj, Authier Hélène, Prat Mélissa, AlaEddine Mohammad, Lefèvre Lise, Rahabi Mouna Chirine, Bernad José, Aubouy Agnès, Bonnafé Elsa, Leprince Jérome, Pipy Bernard, Treilhou Michel, Coste Agnès
UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, Toulouse, France.
IRD, UMR 152, Toulouse, France.
Front Immunol. 2017 Nov 30;8:1650. doi: 10.3389/fimmu.2017.01650. eCollection 2017.
Despite the growing knowledge with regard to the immunomodulatory properties of host defense peptides, their impact on macrophage differentiation and on its associated microbicidal functions is still poorly understood. Here, we demonstrated that the P17, a new cationic antimicrobial peptide from ant venom, induces an alternative phenotype of human monocyte-derived macrophages (h-MDMs). This phenotype is characterized by a C-type lectin receptors (CLRs) signature composed of mannose receptor (MR) and Dectin-1 expression. Concomitantly, this activation is associated to an inflammatory profile characterized by reactive oxygen species (ROS), interleukin (IL)-1β, and TNF-α release. P17-activated h-MDMs exhibit an improved capacity to recognize and to engulf through the overexpression both of MR and Dectin-1. This upregulation requires arachidonic acid (AA) mobilization and the activation of peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor through the leukotriene B4 (LTB4) production. AA/LTB4/PPARγ/Dectin-1-MR signaling pathway is crucial for P17-mediated anti-fungal activity of h-MDMs, as indicated by the fact that the activation of this axis by P17 triggered ROS production and inflammasome-dependent IL-1β release. Moreover, we showed that the increased anti-fungal immune response of h-MDMs by P17 was dependent on intracellular calcium mobilization triggered by the interaction of P17 with pertussis toxin-sensitive G-protein-coupled receptors on h-MDMs. Finally, we also demonstrated that P17-treated mice infected with develop less severe gastrointestinal infection related to a higher efficiency of their macrophages to engulf , to produce ROS and IL-1β and to kill the yeasts. Altogether, these results identify P17 as an original activator of the fungicidal response of macrophages that acts upstream PPARγ/CLRs axis and offer new immunomodulatory therapeutic perspectives in the field of infectious diseases.
尽管人们对宿主防御肽的免疫调节特性的了解日益增加，但其对巨噬细胞分化及其相关杀菌功能的影响仍知之甚少。在此，我们证明了P17（一种来自蚁毒的新型阳离子抗菌肽）可诱导人单核细胞衍生巨噬细胞（h-MDMs）产生一种替代表型。这种表型的特征是由甘露糖受体（MR）和Dectin-1表达组成的C型凝集素受体（CLRs）特征。同时，这种激活与以活性氧（ROS）、白细胞介素（IL）-1β和肿瘤坏死因子-α释放为特征的炎症谱相关。P17激活的h-MDMs通过MR和Dectin-1的过表达表现出更强的识别和吞噬能力。这种上调需要花生四烯酸（AA）的动员以及通过白三烯B4（LTB4）的产生激活过氧化物酶体增殖物激活受体γ（PPARγ）核受体。AA/LTB4/PPARγ/Dectin-1-MR信号通路对于h-MDMs的P17介导的抗真菌活性至关重要，这一事实表明P17对该轴的激活触发了ROS的产生和炎性小体依赖性IL-1β的释放。此外，我们表明P17增强h-MDMs的抗真菌免疫反应依赖于P17与h-MDMs上百日咳毒素敏感的G蛋白偶联受体相互作用触发的细胞内钙动员。最后，我们还证明，用P17处理感染了[具体感染物未给出]的小鼠，其胃肠道感染的严重程度较低，这与其巨噬细胞吞噬[具体吞噬物未给出]、产生活性氧和IL-1β以及杀死酵母的效率较高有关。总之，这些结果确定P17是巨噬细胞杀菌反应的原始激活剂，其作用于PPARγ/CLRs轴的上游，并在传染病领域提供了新的免疫调节治疗前景。
