Alpha-1-Antitrypsin Enhances Primary Human Macrophage Immunity Against Non-tuberculous Mycobacteria
Alpha-1-Antitrypsin Enhances Primary Human Macrophage Immunity Against Non-tuberculous Mycobacteria
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DOI：
10.3389/fimmu.2019.01417
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发表时间：
2019-06-26
影响因子：
7.3
通讯作者：
Chan, Edward D.
中科院分区：
文献类型：
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作者：
Bai, Xiyuan;Bai, An;Chan, Edward D.
基本原理：非结核分枝杆菌肺病和α-1-抗胰蛋白酶（MT）缺乏之间的联系可能部分是由于潜在的肺气肿或支气管扩张。但是越来越多的证据表明MT本身可以增强宿主对微生物病原体的免疫力，因此MT缺乏会损害宿主的保护作用。目的：本项目的目的是确定MT是否可以增强巨噬细胞对非结核分枝杆菌的活性。我们比较了在MT输注前即刻和输注后不久获得的自体血浆中培养的单核细胞衍生的巨噬细胞的能力，测量和主要结果：我们发现，与MT输注前单核细胞衍生的巨噬细胞加血浆相比，巨噬细胞和MT输注一段时间后获得的同期血浆能够显著更好地控制M.胞内感染;减少的细菌负荷与更大的吞噬体-溶酶体融合和增加的自噬体形成/成熟有关，后者是由于MT抑制两种M.细胞内诱导的核因子-κ B活化和A20表达。而M.细胞内感染MT后输注的巨噬细胞和血浆，抑制THP-1细胞、单核细胞衍生的巨噬细胞和肺泡巨噬细胞中的半胱天冬酶-3意外地降低了M.胞内负荷，表明凋亡损害巨噬细胞对M.结论：AAT增强巨噬细胞对M.细胞内感染通过增强吞噬体-溶酶体融合和自噬
Rationale: The association between non-tuberculous mycobacterial lung disease and alpha-1-antitrypsin (MT) deficiency is likely due, in part, to underlying emphysema or bronchiectasis. But there is increasing evidence that MT itself enhances host immunity against microbial pathogens and thus deficiency could compromise host protection.Objectives: The goal of this project is to determine if MT could augment macrophage activity against non-tuberculous mycobacteria.Methods: We compared the ability of monocyte-derived macrophages cultured in autologous plasma that were obtained immediately before and soon after MT infusion-given to individuals with MT deficiency-to control an ex vivo Mycobacterium intracellulare infection.Measurements and Main Results: We found that compared to pre-MT infused monocyte-derived macrophages plus plasma, macrophages, and contemporaneous plasma obtained after a session of MT infusion were significantly better able to control M. intracellulare infection; the reduced bacterial burden was linked with greater phagosome-lysosome fusion and increased autophagosome formation/maturation, the latter due to MT inhibition of both M. intracellulare-induced nuclear factor-kappa B activation and A20 expression. While there was a modest increase in apoptosis in the M. intracellulare-infected post-MT infused macrophages and plasma, inhibiting caspase-3 in THP-1 cells, monocyte-derived macrophages, and alveolar macrophages unexpectedly reduced the M. intracellulare burden, indicating that apoptosis impairs macrophage control of M. intracellulare and that the host protective effects of MT occurred despite inducing apoptosis.Conclusion: AAT augments macrophage control of M. intracellulare infection through enhancing phagosome-lysosome fusion and autophagy