Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases
Autor: | Jiexi Liao, Kazuhiro Furuhashi, Jan M. Herter, Xavier Cullere, Yunfeng Chen, Daniel J. DeAngelo, Gurpanna Saggu, George C. Tsokos, Cheng Zhu, Mark J. Miller, Jeffrey C. Berry, Lihua Yang, Spencer P. Pittman, Hiroshi Nishi, Samantha L. Hamilton, Tanya N. Mayadas, Florencia Rosetti |
---|---|
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Neutrophils Kidney Glomerulus Fc receptor Inflammation HL-60 Cells urologic and male genital diseases Immunoglobulin G 03 medical and health sciences Mice Glomerulonephritis Nitriles medicine Rapidly progressive glomerulonephritis Animals Humans Proto-Oncogene Proteins c-abl Mice Knockout Kidney Aniline Compounds biology Chemistry urogenital system Receptors IgG General Medicine medicine.disease female genital diseases and pregnancy complications Cell biology Capillaries 030104 developmental biology medicine.anatomical_structure src-Family Kinases biology.protein Quinolines medicine.symptom Bosutinib medicine.drug Proto-oncogene tyrosine-protein kinase Src Research Article |
Zdroj: | The Journal of clinical investigation. 127(10) |
ISSN: | 1558-8238 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |