Antimyeloperoxidase antibodies rapidly induce α4-integrin–dependent glomerular neutrophil adhesion

Kuligowski, Michael; Kwan, Rain; Lo, Cecilia W.; Wong, Cyndi; James, Will G.; Bourges, Dorothée; Ooi, Joshua D.; Abeynaike, Latasha D.; Hall, Pam; Kitching, A. Richard; Hickey, Michael J.

doi:10.1182/blood-2008-12-192617

Cited by 46 publications

(44 citation statements)

References 47 publications

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“…4,40 Mice were anesthetized by i.p. injection of a cocktail of 150 mg/kg ketamine hydrochloride (Troy Lab, Smithfield, NSW, Australia) and 10 mg/kg xylazine (Pfizer, West Ryde, NSW, Australia).…”

Section: Renal Intravital Microscopymentioning

confidence: 99%

Platelet Recruitment to the Inflamed Glomerulus Occurs via an αIIbβ3/GPVI-Dependent Pathway

Devi

Kuligowski

Kwan

et al. 2010

The American Journal of Pathology

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Recruitment of leukocytes to glomeruli is fundamental to the pathogenesis of many forms of glomerulonephritis. In a model of glomerulonephritis induced by in situ immune complex deposition, we previously observed that, in addition to leukocytes, platelets accumulate in glomerular capillaries, where they contribute to leukocyte recruitment. However, the mechanisms of platelet recruitment and the role of platelet-expressed P-selectin in leukocyte recruitment require further investigation. We used intravital microscopy to examine the mechanisms of platelet and leukocyte recruitment to glomeruli of mice following administration of an antibody against the glomerular basement membrane (anti-GBM antibody). Platelet recruitment was initiated within five minutes of administration of anti-GBM antibody. This was unaltered by inhibition of platelet GPIb␣ but was prevented by the absence of platelet GPVI. Fibrinogen was deposited in glomerular capillaries via a partially intercellular adhesion molecule 1 (ICAM-1)-dependent mechanism, and inhibition of ␣ IIb ␤ 3 , fibrinogen and ICAM-1 inhibited platelet recruitment. Notably, neutrophil depletion also reduced platelet accumulation, indicating a cooperative interaction underlying recruitment of platelets and neutrophils. Finally, using bone marrow chimeras to restrict expression of P-selectin to platelets or endothelial cells, platelet but not endothelial P-selectin was required for glomerular leukocyte recruitment. Together these data indicate that platelet recruitment in this model is dependent on the combined actions of GPVI and the ␣ IIb ␤ 3 /fibrinogen/ ICAM-1 pathway and that platelet P-selectin is crucial for subsequent leukocyte recruitment. (Am J Pathol

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Section: Renal Intravital Microscopymentioning

confidence: 99%

Platelet Recruitment to the Inflamed Glomerulus Occurs via an αIIbβ3/GPVI-Dependent Pathway

Devi

Kuligowski

Kwan

et al. 2010

The American Journal of Pathology

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“…With use of these model systems, TNF␣, complement, chemokines, and integrins were identified as potential targets. [22][23][24][25][26] We optimized an MPO-ANCA mouse model and showed that the complement receptor C5a and the PI3K␥ isoform are novel targets. 27,28 We used this model to assess NCGN with the 26S proteasome inhibitor bortezomib (BTZ), compared with standard steroid/cyclophosphamide (S/CYC) treatment.…”

mentioning

confidence: 99%

Myeloperoxidase-Specific Plasma Cell Depletion by Bortezomib Protects from Anti-Neutrophil Cytoplasmic Autoantibodies–Induced Glomerulonephritis

Bontscho

Schreiber

Manz

et al. 2011

Journal of the American Society of Nephrology

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Anti-neutrophil cytoplasmic autoantibodies (ANCA) cause vasculitis and necrotizing crescentic glomerulonephritis (NCGN). Steroids and cytotoxic drugs reduce mortality but can cause significant adverse events. The proteasome inhibitor bortezomib (BTZ) prevents glomerulonephritis in mouse models of lupus but its efficacy in ANCA-associated glomerulonephritis is unknown. We induced anti-MPO IgGmediated NCGN by transplanting wild-type bone marrow (BM) into irradiated MPO-deficient mice immunized with MPO. Four weeks after BM transplantation, we treated mice with steroid/cyclophosphamide (S/CYC) or BTZ. Compared with untreated control mice, both S/CYC and BTZ significantly reduced urine abnormalities, NCGN, and infiltration of neutrophils and macrophages. Response to BTZ depended on timing of administration: BTZ abrogated NCGN if begun 3 weeks, but not 5 weeks, after BM transplantation. BTZ treatment significantly reduced total and MPO-specific plasma cells in both the spleen and bone marrow, resulting in significantly reduced anti-MPO titers. Furthermore, BTZ affected neither B cells nor total CD4 and CD8 T cells, including their naive and effector subsets. In contrast, S/CYC reduced the total number of cells in the spleen, including total and MPO-specific plasma cells and B cells. In contrast to BTZ, S/CYC did not affect total and MPO-specific plasma cells in the bone marrow. Three of 23 BTZ-treated mice died within 36 hours after BTZ administration. In summary, BTZ depletes MPO-specific plasma cells, reduces anti-MPO titers, and prevents NCGN in mice.

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“…Infusion of high doses of anti-MPO antibody to LPS-free mice resulted in a glomerular leukocyte adhesion, which was b2-integrin independent, but instead required neutrophil a4-integrin and an unknown ligand distinct from VCAM-1. 20 Human neutrophils do not express a4b1, except in extreme septic conditions, 137 but they express the a9b1-integrin, which has similar specificities. 33,34 (D) Anti-MPO-induced glomerular leukocyte adhesion in LPS-treated mice.…”

Section: Role Of Complementmentioning

confidence: 99%

“…18,19 High concentrations of Fc-reactive ANCA could provide these misleading signals as suggested by the glomerular neutrophil adhesion observed in naïve LPS mice upon the injection of high doses of anti-MPO antibodies. 20 C5a may also play an important role because neutrophils activate complement and release C5a when stimulated by inflammatory cytokines. 21 C5a is a strong neutrophil agonist triggering homotypic aggregation, 22 which is favored by the presence of cell-bound C3 fragments interacting with CR1 and CR3 (Mac-1) receptors, for C3b and iC3b, respectively, on bystander neutrophils.…”

Section: Early Misleading Signals and Homotypic Aggregationmentioning

confidence: 99%

“…138 TNF-primed neutrophils, bearing anti-MPO antibodies, adhere to the endothelium of glomerular capillaries, via the b2-integrin LFA-1 interacting with endothelial ICAM-1. 20 Transfer from Innate to Adaptive Immune Response Neutrophils are a key component of innate immunity and contribute to the crucial decision to set up an adaptive immune response. 112 As shown in Figure 6B, neutrophils recruit dendritic cells, monocytes, and lymphocytes, which are important in the promotion of granuloma formation 113 and autoimmunity in AAV.…”

Section: Role Of Complementmentioning

confidence: 99%

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Endothelium-Neutrophil Interactions in ANCA-Associated Diseases

Halbwachs

Lesavre

2012

Journal of the American Society of Nephrology

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The two salient features of ANCA-associated vasculitis (AAV) are the restricted microvessel localization and the mechanism of inflammatory damage, independent of vascular immune deposits. The microvessel localization of the disease is due to the ANCA antigen accessibility, which is restricted to the membrane of neutrophils engaged in b2-integrin-mediated adhesion, while these antigens are cytoplasmic and inaccessible in resting neutrophils. The inflammatory vascular damage is the consequence of maximal proinflammatory responses of neutrophils, which face cumulative stimulations by TNF-a, b2-integrin engagement, C5a, and ANCA by the FcgRII receptor. This results in the premature intravascular explosive release by adherent neutrophils of all of their available weapons, normally designed to kill IgG-opsonized bacteria after migration in infected tissues.

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Antimyeloperoxidase antibodies rapidly induce α4-integrin–dependent glomerular neutrophil adhesion

Cited by 46 publications

References 47 publications

Platelet Recruitment to the Inflamed Glomerulus Occurs via an αIIbβ3/GPVI-Dependent Pathway

Platelet Recruitment to the Inflamed Glomerulus Occurs via an αIIbβ3/GPVI-Dependent Pathway

Myeloperoxidase-Specific Plasma Cell Depletion by Bortezomib Protects from Anti-Neutrophil Cytoplasmic Autoantibodies–Induced Glomerulonephritis

Endothelium-Neutrophil Interactions in ANCA-Associated Diseases

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