Nitrogen-containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)-mediated and interleukin 1β (IL-1β)-mediated production of neutrophil extracellular traps (NETs)
Nitrogen-containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)-mediated and interleukin 1β (IL-1β)-mediated production of neutrophil extracellular traps (NETs)
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DOI：
10.1002/jbmr.4384
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发表时间：
2021-06-22
影响因子：
6.2
通讯作者：
Endo, Yasuo
中科院分区：
文献类型：
--
作者：
Bando, Kanan;Kuroishi, Toshinobu;Endo, Yasuo
在双膦酸盐（BPs）中，含氮BPs（N-BPs）比非N-BPs具有更强的抗骨吸收作用。然而，N-BP具有各种副作用，如首次给药后的急性流感样反应和重复给药后的颌骨骨坏死。这种影响的机制尚不清楚。为了克服这些问题，重要的是描绘N-BP的炎症性质。在这里，我们分析了N-BP阿仑膦酸钠（Ale）和唑来膦酸盐（Zol）诱导的小鼠耳廓炎症反应。我们发现以下内容：（i）Ale和Zol各自诱导两个阶段的炎症（早期弱耳肿胀和晚期强耳肿胀）;（ii）两个阶段均被脂多糖增强（LPS;革兰氏阴性菌的细胞表面成分，包括口腔细菌），但被溶质载体磷酸盐转运蛋白抑制剂阻止20/34（SLC 20/SLC 34）;（iii）巨噬细胞和中性粒细胞参与了Ale+ LPS诱导的耳肿胀的两个阶段;（iv）Ale增加或倾向于增加各种细胞因子，而LPS增强了这些作用，尤其是对白细胞介素1 β的作用（v）三磷酸腺苷（ATP）参与了这两个阶段，并且单独的Ale或Ale+LPS增加了耳耳廓中的ATP;（vi）由Ale+LPS诱导的增强的晚期肿胀依赖于IL-1和中性粒细胞胞外陷阱（NETs;嗜中性粒细胞衍生的网状复合物）;（vii）嗜中性粒细胞与巨噬细胞和树突细胞一起也起产生IL-1 β的细胞的作用，并且在用IL-1 β刺激时，嗜中性粒细胞产生NET;（viii）ATP诱导的IL-1 β刺激耳鼻咽部的嘌呤能2X 7（P2 X7）受体;（ix）Ale+LPS也在牙龈中证实了NET形成。这些结果表明（i）N-BP通过ATP产生和P2 X7受体刺激诱导早期和晚期炎症;（ii）N-BP和LPS通过ATP介导的中性粒细胞、巨噬细胞和/或树突状细胞产生IL-1 β诱导相互增强的早期和晚期反应;和（iii）IL-1 β刺激的中性粒细胞产生NET可能介导晚期，导致炎症延长。这些结果进行了讨论与N-BP治疗的患者中看到的副作用。(c)2021年美国骨与矿物质研究学会（ASBMR）。
Among the bisphosphonates (BPs), nitrogen-containing BPs (N-BPs) have much stronger anti-bone-resorptive actions than non-N-BPs. However, N-BPs have various side effects such as acute influenza-like reactions after their initial administration and osteonecrosis of the jawbones after repeated administration. The mechanisms underlying such effects remain unclear. To overcome these problems, it is important to profile the inflammatory nature of N-BPs. Here, we analyzed the inflammatory reactions induced in mouse ear pinnae by the N-BPs alendronate (Ale) and zoledronate (Zol). We found the following: (i) Ale and Zol each induced two phases of inflammation (early weak and late strong ear swelling); (ii) both phases were augmented by lipopolysaccharides (LPSs; cell-surface constituent of gram-negative bacteria, including oral bacteria), but prevented by inhibitors of the phosphate transporters of solute carrier 20/34 (SLC20/SLC34); (iii) macrophages and neutrophils were involved in both phases of Ale+LPS-induced ear-swelling; (iv) Ale increased or tended to increase various cytokines, and LPS augmented these effects, especially that on interleukin 1 beta (IL-1 beta); (v) adenosine triphosphate (ATP) was involved in both phases, and Ale alone or Ale+LPS increased ATP in ear pinnae; (vi) the augmented late-phase swelling induced by Ale+LPS depended on both IL-1 and neutrophil extracellular traps (NETs; neutrophil-derived net-like complexes); (vii) neutrophils, together with macrophages and dendritic cells, also functioned as IL-1 beta-producing cells, and upon stimulation with IL-1 beta, neutrophils produced NETs; (viii) stimulation of the purinergic 2X7 (P2X7) receptors by ATP induced IL-1 beta in ear pinnae; (ix) NET formation by Ale+LPS was confirmed in gingiva, too. These results suggest that (i) N-BPs induce both early-phase and late-phase inflammation via ATP-production and P2X7 receptor stimulation; (ii) N-BPs and LPS induce mutually augmenting responses both early and late phases via ATP-mediated IL-1 beta production by neutrophils, macrophages, and/or dendritic cells; and (iii) NET production by IL-1 beta-stimulated neutrophils may mediate the late phase, leading to prolonged inflammation. These results are discussed in relation to the side effects seen in patients treated with N-BPs. (c) 2021 American Society for Bone and Mineral Research (ASBMR).