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Abstract: FR-OR37

Leukotriene B4-BLT1 Axis Controls Neutrophil Accumulation via Fcγ Receptor-Dependent Leukotriene B4 Production in Experimental Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Shioda, Ryotaro, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Jo, Airi, Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan
  • Nakayama, Maiko, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Suzuki, Yusuke, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
Background

Eicosanoids are biologically active lipid mediators generated rapidly at sites of inflammation. Leukotrienes are one of the eicosanoids generated through the metabolism of arachidonic acid by 5-lipoxygenase and LTA4 hydrolase. Although it is generally known that leukotriene B4 (LTB4) functions as a potent chemotactic factor for neutrophils via its receptor BLT1, the role of LTB4-BLT1 axis on glomerulonephritis has not been clarified.

Methods

We used the nephrotoxic serum nephritis model, which mimics human glomerulonephritis. To investigate the effect of LTB4-BLT1 axis on glomerulonephritis, we used BLT1-knock out (KO) mice. Specifically, serological and histological analyses were performed in acute and chronic phases. We used LC/MS/MS to measure LTB4 in the kidney. To confirm LTB4 production by neutrophils, we activated the Fcγ receptor of neutrophils by cross-linking with IgG.

Results

On day 7 after onset of nephritis, wild-type (WT) mice showed severe proteinuria, crescent formation accompanied by macrophage infiltration, which was markedly attenuated in BLT1-KO mice. Next, we examined neutrophil infiltration in glomeruli in acute phase; the number of neutrophils in glomeruli peaked at 6 hours after onset both in WT and BLT1-KO mice, but was markedly lower in BLT1-KO mice. Complement activity and chemokines were comparable in both groups. Then, we measured LTB4 in the kidney and found that LTB4 production occurred within an hour of onset, indicating a dominant effect of the LTB4-BLT1 axis on early neutrophil infiltration. In vitro studies demonstrated that LTB4 production was dependent on activation of Fcγ receptors. On day 1 after onset, BLT1-KO mice exhibited reduced proteinuria and attenuated endothelial damage. Furthermore, administration of BLT1 receptor antagonists after onset relieved nephritis, strongly indicating its therapeutic effect. Finally, BLT1-positive cells infiltrated glomeruli of patients with ANCA-associated vasculitis, suggesting that the LTB4-BLT1 axis might play important roles in human glomerulonephritis.

Conclusion

Our results revealed that blockage of initial neutrophil infiltration by inhibition of the LTB4-BLT1 axis mitigated nephritis and could counteract subsequent macrophage infiltration. The LTB4-BLT1 might be a promising therapeutic target for glomerulonephritis.