当前位置: X-MOL 学术J. Clin. Invest. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2017-09-11 , DOI: 10.1172/jci94039
Hiroshi Nishi , Kazuhiro Furuhashi , Xavier Cullere , Gurpanna Saggu , Mark J. Miller , Yunfeng Chen , Florencia Rosetti , Samantha L. Hamilton , Lihua Yang , Spencer P. Pittman , Jiexi Liao , Jan M. Herter , Jeffrey C. Berry , Daniel J. DeAngelo , Cheng Zhu , George C. Tsokos , Tanya N. Mayadas

The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor FcγRIIA promotes glomerular neutrophil accumulation and damage in anti–glomerular basement membrane–induced (anti-GBM–induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through FcγRIIA-dependent, Abl/Src tyrosine kinase–mediated F-actin polymerization. Biophysical measurements showed that the lifetime of FcγRIIA-IgG bonds increased under mechanical force in an F-actin–dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil FcγRIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced FcγRIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.

中文翻译:

嗜中性粒细胞的Fc γ RIIA促进经由Abl的/ Src的激酶IgG介导的嗜中性粒细胞的肾小球捕获

肾小球毛细血管是感染后迅速进展的肾小球肾炎中免疫复合物沉积和随后的中性粒细胞积累的常见部位。然而,嗜中性粒细胞募集的机制仍然是神秘的,并且没有针对性的疗法来避免肾小球炎症反应中的这种近端事件。当在鼠嗜中性粒细胞上表达时,独特的人类活化性Fc受体FcγRIIA促进肾小球中性粒细胞的积累和抗肾小球基底膜诱导(抗GBM诱导)的肾小球肾炎的损害。在这里,我们发现嗜中性粒细胞是在体外固定的IgG抗体通过FcγRIIA依赖性,Abl / Src酪氨酸激酶介导的F-肌动蛋白聚合反应直接被固定的IgG抗体捕获的。生物物理测量结果显示,在机械力作用下,FcγRIIA-IgG键的寿命以F-肌动蛋白依赖性方式增加,这可以在生理流下捕获嗜中性粒细胞。肾脏活体显微镜检查显示,直径与肾小球毛细血管相似的循环中性粒细胞在通过中性粒细胞FcγRIIA和Abl / Src激酶沉积抗GBM抗体后突然停止。因此,在实验性新月形抗GBM肾炎中,用波舒替尼抑制Abl / Src可减少FcγRIIA介导的肾小球中性粒细胞积聚和肾损伤。这些数据确定了IgG沉积后博舒替尼可能靶向中性粒细胞在肾小球毛细血管内募集的途径,以避免肾小球损伤。可以在生理流下捕获嗜中性粒细胞。肾脏活体显微镜检查显示,直径与肾小球毛细血管相似的循环中性粒细胞在通过中性粒细胞FcγRIIA和Abl / Src激酶沉积抗GBM抗体后突然停止。因此,在实验性新月形抗GBM肾炎中,用波舒替尼抑制Abl / Src可减少FcγRIIA介导的肾小球中性粒细胞积聚和肾损伤。这些数据确定了IgG沉积后博舒替尼可能靶向中性粒细胞在肾小球毛细血管内募集的途径,以避免肾小球损伤。可以在生理流下捕获嗜中性粒细胞。肾脏活体显微镜检查显示,直径与肾小球毛细血管相似的循环中性粒细胞在通过中性粒细胞FcγRIIA和Abl / Src激酶沉积抗GBM抗体后突然停止。因此,在实验性新月形抗GBM肾炎中,用波舒替尼抑制Abl / Src可减少FcγRIIA介导的肾小球中性粒细胞积聚和肾损伤。这些数据确定了IgG沉积后博舒替尼可能靶向中性粒细胞在肾小球毛细血管内募集的途径,以避免肾小球损伤。在通过中性粒细胞FcγRIIA和Abl / Src激酶的抗GBM抗体沉积后突然停止。因此,在实验性新月形抗GBM肾炎中,用波舒替尼抑制Abl / Src可减少FcγRIIA介导的肾小球中性粒细胞积聚和肾损伤。这些数据确定了IgG沉积后博舒替尼可能靶向中性粒细胞在肾小球毛细血管内募集的途径,以避免肾小球损伤。在通过中性粒细胞FcγRIIA和Abl / Src激酶的抗GBM抗体沉积后突然停止。因此,在实验性新月形抗GBM肾炎中,用波舒替尼抑制Abl / Src可减少FcγRIIA介导的肾小球中性粒细胞积聚和肾损伤。这些数据确定了IgG沉积后博舒替尼可能靶向中性粒细胞在肾小球毛细血管内募集的途径,以避免肾小球损伤。
更新日期:2017-10-03
down
wechat
bug