Myeloid CFTR loss-of-function causes persistent neutrophilic inflammation in cystic fibrosis.
Myeloid CFTR loss-of-function causes persistent neutrophilic inflammation in cystic fibrosis.
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DOI：
10.1002/jlb.3a0520-193rr
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发表时间：
2020-12
影响因子：
5.5
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Ng HP;Jennings S;Wellems D;Sun F;Xu J;Nauseef WM;Wang G
持续性嗜酸性炎症是囊性纤维化（CF）的标志。然而，这种突出的病理机制仍然不完全清楚。在这里，我们报告，CFTR在骨髓免疫细胞中起着关键作用，在控制嗜酸性炎症。用不同剂量的酵母多糖颗粒对髓系CFTR敲除（Mye-Cftr−/−）小鼠和同源野生型（WT）小鼠进行腹膜攻击，产生不同严重程度的无菌性腹膜炎。高剂量激发导致Mye-Cftr−/−小鼠的死亡率显著升高，表明骨髓细胞缺乏CFTR的小鼠在宿主炎症控制方面存在内在缺陷。低剂量激发表明Mye-Cftr−/−小鼠的炎症消退受损，这反映在促炎细胞因子（包括中性粒细胞趋化因子MIP-2和KC）的显著过量产生以及中性粒细胞的持续蓄积。追踪体内中性粒细胞动员表明，髓样CF小鼠募集的中性粒细胞显著多于WT小鼠。酵母多糖肺激发引起肺中的旺盛炎症，并概括了腹膜激发的结果。为了确定主要负责中性粒细胞过度募集的主要类型的细胞，我们纯化并培养离体酵母多糖诱导的腹膜中性粒细胞和巨噬细胞。CF中性粒细胞产生的MIP-2显著多于WT对应物，并且从髓样CF小鼠分离的外周血中性粒细胞在酵母聚糖体外刺激后也产生显著更多的MIP-2。这些数据共同表明，在没有感染的情况下，骨髓免疫细胞，特别是嗜中性粒细胞中的CFTR功能障碍导致过度炎症和过度的嗜中性粒细胞动员。因此，继发于骨髓细胞中CFTR异常或缺失的失调性炎症可能是临床观察到的CF中嗜酸性炎症的基础。囊性纤维化（CF）嗜中性粒细胞缺乏次氯酸（HOCl）产生，导致炎性激动剂的缓慢失活、延长的刺激、更多的细胞因子产生和更严重的炎症。
Persistent neutrophilic inflammation is a hallmark of cystic fibrosis (CF). However, the mechanisms underlying this outstanding pathology remain incompletely understood. Here we report that CFTR in myeloid immune cells plays a pivotal role in control of neutrophilic inflammation. Myeloid CFTR-Knockout (Mye-Cftr−/−) mice and congenic wild-type (WT) mice were challenged peritoneally with zymosan particles at different doses, creating aseptic peritonitis with varied severity. A high-dose challenge resulted in significantly higher mortality in Mye-Cftr−/− mice, indicating an intrinsic defect in host control of inflammation in mice whose myeloid cells lack CFTR. The low-dose challenge demonstrated an impaired resolution of inflammation in Mye-Cftr−/− mice, reflected by a significant over-production of pro-inflammatory cytokines, including neutrophil chemokines MIP-2 and KC, and sustained accumulation of neutrophils. Tracing neutrophil mobilization in vivo demonstrated that myeloid CF mice recruited significantly more neutrophils than did WT mice. Pulmonary challenge with zymosan elicited exuberant inflammation in the lung and recapitulated the findings from peritoneal challenge. To determine the major type of cell that was primarily responsible for the over-recruitment of neutrophils, we purified and cultured ex vivo zymosan-elicited peritoneal neutrophils and macrophages. The CF neutrophils produced significantly more MIP-2 than did the WT counterparts, and peripheral blood neutrophils isolated from myeloid CF mice also produced significantly more MIP-2 after zymosan stimulation in vitro. These data altogether suggest that CFTR dysfunction in myeloid immune cells, especially neutrophils, leads to hyper-inflammation and excessive neutrophil mobilization in the absence of infection. Thus, dysregulated inflammation secondary to abnormal or absent CFTR in myeloid cells may underlie the clinically observed neutrophilic inflammation in CF. Cystic fibrosis (CF) neutrophils are deficient in hypochlorous acid (HOCl) production, leading to slow inactivation of inflammatory agonists, prolonged stimulation, more production of cytokines, and greater inflammation.