Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases
Hiroshi Nishi, … , George C. Tsokos, Tanya N. Mayadas
Hiroshi Nishi, … , George C. Tsokos, Tanya N. Mayadas
Published September 11, 2017
Citation Information: J Clin Invest. 2017;127(10):3810-3826. https://doi.org/10.1172/JCI94039.
View: Text | PDF
Research Article Inflammation Nephrology

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

  • Text
  • PDF
Abstract

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.

Authors

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

×

Figure 5

In vivo neutrophil trafficking in glomerular capillaries at steady state and after anti-GBM treatment in LysM-GFP mice.

Options: View larger image (or click on image) Download as PowerPoint
In vivo neutrophil trafficking in glomerular capillaries at steady state...
In vivo 2-photon time-lapse imaging of glomeruli in untreated LysM-GFP mice at steady state (untreated, control) and 1.5–2 hours after anti-GBM (αGBM) treatment (n = 3 mice, 5 glomeruli for control; n = 4 mice, 6 glomeruli for αGBM). Imaging parameters were set to preferentially visualize GFP+ neutrophils (see Supplemental Figure 4A). (A and B) Glomerular capillaries (GC, red, Q-dot 565) and neutrophils (Np, green, LysM-GFP) in a control (left) and αGBM-treated (right) mouse are shown (A). Capillary lumen and neutrophil diameters were calculated and found to be similar in size with no significant differences between control and αGBM groups (B) by a 2-tailed unpaired t test. (C) The mean ± SEM of neutrophils per glomerulus (glm) (arrows) in untreated and αGBM-treated LysM-GFP mice were counted at 0 and 9 minutes, and representative images are shown. SHG, second-harmonic generation. Scale bars: 25 μm (A), 50 μm (C). (D) Distributions of glomerular duration times for control and αGBM groups plotted in minutes. Duration times were clearly non-normal, and control and αGBM groups were significantly different using a 2-tailed Mann-Whitney U test, P < 0.01. (E) Distributions using a 2-sample Kolmogorov-Smirnov (KS) test comparison percentile plot. The group duration time distributions were significantly different using a KS test, P < 0.01, D = 0.3813. (F) A bar graph of mean ± SEM is shown to provide a sense of scale for the dwell times. *P < 0.01 by 2-tailed unpaired t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts