Abstract: SA-PO587
Neutrophil Elastase-Deficient Mice Are Protected from Experimental Myeloperoxidase Anti-Neutrophil Cytoplasmic Antibody Vasculitis
Session Information
- Glomerular Diseases: Immunology, Inflammation - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- O'Sullivan, Kim M., Monash University, Clayton, Victoria, Australia
- Gan, Poh-Yi, Monash University, Monash Medical Centre, Melbourne, Victoria, Australia
- Kitching, A. Richard, Monash University, Monash Health, Clayton, Victoria, Australia
- Holdsworth, Stephen R., Monash Health, Clayton, Victoria, Australia
Group or Team Name
- Autoimmune Kidney Disease and Vasculitis Research Group
Background
Neutrophil extracellular trap (NETs) are implicated in the pathogenesis of myeloperoxidase anti neutrophil cytoplasmic antibody vasculitis (MPO-AAV). Neutrophil elastase (NE) is implicated in initiating NET formation through proteolytic degradation of the nuclear envelope, histone degradation and chromatin decondensation in concert with other neutrophil enzymes to facilitate DNA release. NETs are decorated with multiple proinflammatory enzymes including MPO (the autoantigen in this disease) and NE. NE released through degranulation is degraded by endogenous NE inhibitors, however NE bound to NET derived DNA is protected providing a reservoir of proteolytic NE enabling tissue destruction, microvascular injury and further recruitment of neutrophils. This study investigates the pathogenic contribution of NE release through NET formation in experimental MPO-AAV using animals deficient in neutrophil elastase.
Methods
A 20 day experimental model of anti-MPO GN was induced in B6.129X1-Elanetm1Sds/J mice (neutrophil elastase knock out mice) and wild-type (WT) litter mate controls by myeloperoxidase (MPO) immunisation and GN triggered using a sub-nephritogenic dose of anti-glomerular basement membrane globulin (anti GBM Ig), [n=10 (WT) and n=10 (Elane-/-)].
Results
Elane-/- animals were protected from excessive NET production and glomerular injury with significantly reduced numbers of glomerular neutrophils, extracellular MPO deposition, CD4 T cells and macrophages influx (all, P <0.05 compared to WT). Histological assessment of kidneys demonstrated a reduction in segmental necrosis in the Elane-/- group compared to the WT group (P<0.05). Functional injury measured by creatinine/albuminuria ratio was significantly reduced in the Elane -/- group compared to the WT group (P=0.04). Systemic autoimmunity to MPO was significantly reduced in Elane-/- mice with reduced frequency of MPO specific CD4 effector T cells from the draining lymph nodes and a significant reduction in dermal DTH, measured by a 24 hour footpad challenge with MPO (P<0.05, compared with WT).
Conclusion
Reduced NET formation in Elane -/- mice attenuated glomerular injury through the reduction in NET associated MPO and NE. This data provides proof of concept evidence that targeting NE therapeutically may be of potential benefit in MPO-AAV.