C5a Receptor Mediates Neutrophil Activation and ANCA-Induced Glomerulonephritis

Self Cite

ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1b generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91 phox -deficient or p47 phox -deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1b levels compared with mice transplanted with wild-type bone marrow. IL-1b receptor blockade abrogated aggravated NCGN in gp91 phox -deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1b generation in gp91 phox -deficient and p47 phox -deficient monocytes compared with wild-type monocytes. This enhanced IL-1b generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1b generation were inversely related in human monocytes. Furthermore, transplantation of gp91 phox /caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91 phox bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.

Section: Methodsmentioning

confidence: 99%

“…53 Monocytes were pretreated with 5 mg/ml cytochalasin B for 15 minutes. Cells (0.75310 6 ) were pretreated with SOD (300 units/ml) and catalase (300 units/ml) for 15 minutes and primed with 2 ng/ml TNF-a for 15 minutes before 10 mg/ml mAbs (either isotype or MPO-specific) were added.…”

Section: Measurement Of Respiratory Burst By Reduction Of Ferricytochmentioning

confidence: 99%

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

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“…93 Complement-mediated cytotoxicity is another trigger for glomerular necroinflammation. 94 Glomerular cell necrosis induces DAMP release that further drives cytokine and chemokine release, leukocyte recruitment, and inflammation. 92 Infiltrating immune cells, in turn, further contribute to necroinflammation by NETosis (neutrophils), 92 cytokine-induced cell death (all proinflammatory leukocytes), 95 or direct T cell-related cytotoxicity.…”

Section: Rapidly Progressive Gnmentioning

confidence: 99%

Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

189

185

The bidirectional causality between kidney injury and inflammation remains an area of unexpected discoveries. The last decade unraveled the molecular mechanisms of sterile inflammation, which established danger signaling via pattern recognition receptors as a new concept of kidney injury-related inflammation. In contrast, renal cell necrosis remained considered a passive process executed either by the complement-related membrane attack complex, exotoxins, or cytotoxic T cells. Accumulating data now suggest that renal cell necrosis is a genetically determined and regulated process involving specific outside-in signaling pathways. These findings support a unifying theory in which kidney injury and inflammation are reciprocally enhanced in an autoamplification loop, referred to here as necroinflammation. This integrated concept is of potential clinical importance because it offers numerous innovative molecular targets for limiting kidney injury by blocking cell death, inflammation, or both. Here, the contribution of necroinflammation to AKI is discussed in thrombotic microangiopathies, necrotizing and crescentic GN, acute tubular necrosis, and infective pyelonephritis or sepsis. Potential new avenues are further discussed for abrogating necroinflammation-related kidney injury, and questions and strategies are listed for further exploration in this evolving field.

“…[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. BTZ is approved for use in multiple myeloma and was recently effective in preventing glomerulonephritis in the NZB/W and MRL/lpr lupus mouse model.…”

mentioning

confidence: 99%

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

Bontscho

Schreiber

Manz

et al. 2011

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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.