Endogenous myeloperoxidase promotes neutrophil-mediated renal injury, but attenuates T cell immunity inducing crescentic glomerulonephritis.
Myeloperoxidase (MPO) is an enzyme that is found in neutrophils and monocytes/macrophages. Intracellularly, it plays a major role in microbial killing, but extracellularly, it may cause host tissue damage. The role of endogenous MPO was studied during neutrophil-mediated (heterologous) and T helper 1 (Th1)/macrophage-mediated (autologous) phases of crescentic glomerulonephritis. Glomerulonephritis was induced in C57BL/6 wild-type (WT) and MPO-deficient (MPO(-/-)) mice by intravenous injection of sheep anti-mouse glomerular basement membrane globulin. MPO activity was increased in kidneys of WT mice during both the heterologous and autologous phases of glomerulonephritis. During the heterologous phase of glomerulonephritis, proteinuria was decreased, whereas glomerular neutrophil accumulation and P-selectin expression were enhanced in MPO(-/-) mice. In the autologous, crescentic phase of glomerulonephritis, MPO(-/-) mice had increased accumulation of CD4(+) cells and macrophages in glomeruli compared with WT mice. However, no difference in renal injury (crescent formation, proteinuria, and serum creatinine levels) was observed. Neutrophils and macrophages from MPO(-/-) mice exhibited reduced production of reactive oxygen species. Assessment of systemic immunity to sheep globulin showed that MPO(-/-) mice had increased splenic CD4(+) cell proliferation, cytokine production, and dermal delayed-type hypersensitivity, as well as enhanced levels of circulating IgG, IgG1, and IgG3. MPO(-/-) mice also had an augmented Th1:Th2 ratio compared with WT mice (IFN-gamma:IL-4 and IgG3:IgG1 ratios). These results suggest that endogenous MPO locally contributes to glomerular damage during neutrophil-mediated glomerulonephritis, whereas it attenuates initiation of the adaptive immune response inducing crescentic, autologous-phase glomerulonephritis by suppressing T cell proliferation, cytokine production, and Th1:Th2 ratio.
Odobasic
Dragana
D
Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Level 5 Block E, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Kitching
A Richard
AR
Semple
Timothy J
TJ
Holdsworth
Stephen R
SR
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D050533:Glomerular Basement Membrane / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*; D011507:Proteinuria / Q000503:physiopathology; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D007074:Immunoglobulin G; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase