Macrolides Promote CCL2-Mediated Macrophage Recruitment and Clearance of Nasopharyngeal Pneumococcal Colonization in Mice
Macrolides Promote CCL2-Mediated Macrophage Recruitment and Clearance of Nasopharyngeal Pneumococcal Colonization in Mice
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DOI：
10.1093/infdis/jiv157
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发表时间：
2015-10-01
影响因子：
6.4
通讯作者：
Kohno, Shigeru
中科院分区：
文献类型：
--
作者：
Iwanaga, Naoki;Nakamura, Shigeki;Kohno, Shigeru
背景肺炎链球菌（肺炎球菌）定植于上呼吸道（URT）的粘膜表面，导致侵袭性疾病。已知大环内酯类具有免疫调节作用。我们研究了大环内酯类药物通过激活宿主先天免疫来减少肺炎球菌定植的效力。经鼻接种肺炎球菌后，评估了URT中的定植动力学、细胞反应和炎性细胞因子水平。EM 900（一种新型的12元非抗生素大环内酯类药物，具有免疫调节作用）在整个实验过程中口服给药。评估10天的存活率。通过酶联免疫吸附试验测定大环内酯介导的腹腔巨噬细胞CCL 2的产生。通过蛋白质印迹和基因沉默试验分析细胞信号通路。肺炎链球菌接种后14天，EM 900治疗的小鼠肺炎链球菌显着减少。促进巨噬细胞募集和Ccl 2信使RNA表达。大环内酯类药物显著诱导腹腔巨噬细胞产生CCL 2，并依赖于通过髓样分化初级反应基因88或含TIR结构域的接头诱导干扰素β介导途径的NF-κ B磷酸化。EM 900预处理可改善侵袭性肺炎球菌病小鼠的死亡率。大环内酯类药物可能通过促进巨噬细胞介导的先天免疫，加速肺炎球菌鼻咽定植的清除，从而抑制侵袭性肺炎球菌感染。
Background. Streptococcus pneumoniae (pneumococcus) colonizes mucosal surfaces of the upper respiratory tract (URT), resulting in invasive disease. Macrolides are known for their immunomodulatory effects. We investigated the potency of macrolides to reduce pneumococcal colonization by activating host innate immunity.Methods. The kinetics of colonization, cellular response, and inflammatory cytokine levels in the URT were assessed after nasal inoculation of pneumococci. EM900 (a novel 12-membered nonantibiotic macrolide with an immunomodulatory effect) was orally administered throughout the experiment. Survival was evaluated for 10 days. Macrolide-mediated CCL2 production from peritoneal macrophages was determined by enzyme-linked immuosorbent assay. The cell-signaling pathway was analyzed by means of Western blotting and gene silencing assays.Results. Streptococcus pneumoniae was significantly reduced from EM900-treated mice 14 days after pneumococcal inoculation. Macrophage recruitment and Ccl2 messenger RNA expression were promoted. CCL2 production from peritoneal macrophages was significantly induced by macrolides and was dependent on NF-kappa B phosphorylation through the myeloid differentiation primary-response gene 88- or TIR domain-containing adapter-inducing interferon-beta-mediated pathway. Mortality of mice with invasive pneumococcal disease was improved by pretreatment with EM900.Conclusions. Macrolides may inhibit invasive pneumococcal infections by accelerating the clearance of pneumococcal nasopharyngeal colonization via promotion of macrophage-mediated innate immunity.