Th17 Cells Promote Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Gan, Poh-Yi; Steinmetz, Oliver M.; Tan, Dunlin; O’Sullivan, Kim M.; Ooi, Joshua D.; Iwakura, Yoichiro; Kitching, A. Richard; Holdsworth, Stephen R.

doi:10.1681/asn.2009070763

Cited by 151 publications

(150 citation statements)

References 35 publications

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“…Abnormalities included glomerular hypercellularity, crescent formation, fibrinoid necrosis, segmental proliferation, hyalinosis, and capillary wall thickening. Fibrin staining was performed on paraffin-cut sections using rabbit anti-mouse fibrinogen (R-4025; a gift from Dr. J. Degen, Children's Research Foundation, Cincinnati, OH) with an ABC kit (DakoCytomation) using diaminobenzidine (Sigma-Aldrich) (23). Thirty consecutive glomeruli were scored per mouse, and the results were expressed as the percentage of glomeruli with fibrin deposition.…”

Section: Methodsmentioning

confidence: 99%

“…Mice administered MPO alone (or in combination with an adjuvant) do not develop glomerulonephritis spontaneously and require a trigger. We used sheep anti-mouse GBM globulin at a subnephritogenic dose, which does not induce significant renal injury if injected alone but will trigger renal injury in mice with autoimmunity to MPO (10,23). Mice were immunized with the control antigen (OVA), MPO alone, MPO and TLR-2 ligand, or MPO and TLR-9 ligand.…”

Section: Amplification Of Glomerular Injury By Tlrenhanced Mpo Autoimmentioning

confidence: 99%

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Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Summers¹,

Steinmetz²,

Gan³

et al. 2011

Arthritis & Rheumatism

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Objective. Autoantibodies constitute the hallmark of antineutrophil cytoplasmic antibody-associated vasculitis (AAV); however, CD4؉ T cells play an essential role in the development of autoimmunity. Infection is associated with vasculitis, with Toll-like receptors (TLRs) a potential link between infection and autoimmunity. This study was undertaken to investigate the role of TLR ligation on cellular and humoral autoimmunity and glomerular injury in experimental myeloperoxidase (MPO)-induced AAV.Methods. We analyzed autoimmune responses in wild-type mice immunized with MPO alone or coimmunized with MPO and a TLR-2 or TLR-9 ligand. The major vascular injury found in human disease, glomerulonephritis with focal necrosis, was triggered by administering a subnephritogenic dose of nephrotoxic serum.Results. MPO alone induced low-titer antineutrophil cytoplasmic antibodies (ANCAs) without delayedtype hypersensitivity or CD4 cytokine responses. However, when MPO was given with either TLR ligand, cellular and humoral autoimmunity was enhanced, but with distinctly different CD4 subsets and IgG ANCA isotypes. TLR-2 ligand induced Th17 autoimmunity, with retinoic acid receptor-related orphan nuclear receptor ␥t-dependent interleukin-17A (IL-17A) production. TLR-9 ligand promoted Th1 autoimmunity, with enhanced production of interferon-␥ (IFN␥) and Th1-associated IgG subclasses. Glomerular vasculitis developed only after the administration of nephrotoxic serum in mice immunized with either TLR ligand and MPO. Glomerulonephritis directed by MPO and TLR-2 ligation was attenuated when IL-17A was neutralized, while glomerulonephritis induced by MPO and TLR-9 ligation was attenuated when IFN␥ was neutralized.Conclusion. Our findings indicate a pathogenic role of TLRs in initiating autoimmune AAV. TLR-2 induces Th17 CD4 cells while TLR-9 can also direct vasculitis, by directing Th1 autoimmunity.

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Section: Methodsmentioning

confidence: 99%

Section: Amplification Of Glomerular Injury By Tlrenhanced Mpo Autoimmentioning

confidence: 99%

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Summers¹,

Steinmetz²,

Gan³

et al. 2011

Arthritis & Rheumatism

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“…MCP-1/CCL2, RANTES/CCL5, MIP-1␣/CCL3, and MIP-1␤/CCL4 are the most commonly described chemokines used in the recruitment of monocyte/macrophages during renal inflammation. 11,35 The corresponding receptors mediate firm adhesion (CCR1), shape change (CCR2 and CCR5), spreading (CCR2 and CCR5), and transmigration. 11 A critical role for chemokine signaling in macrophage infiltration is demonstrated by a number of functional blocking experiments.…”

Section: Role Of CCL and Cxc3l Families In Akimentioning

confidence: 99%

“…55,87 In a mouse model of crescentic glomerulonephritis, upregulation of renal CCR5 ligands (MIP-1␣/CCL3, MIP-1␤/CCL4, and RANTES/CCL5) correlates with the recruitment of monocytes and T cells, 88,35 suggesting a close link between the CCL chemokines and cellmediated immune responses. This notion is further confirmed by finding that CCR5 null mice have an increased renal Th1 response.…”

Section: Role Of Chemokines In T Cell Infiltration During Kidney Injurymentioning

confidence: 99%

Chemokines in Renal Injury

Chung

Lan

2011

Journal of the American Society of Nephrology

237

181

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Renal inflammation underlies many chronic kidney diseases and the infiltration of leukocytes mediates much of the nephritogenic inflammatory response. As several recent reviews have dealt with the basic biology, mouse models, and blockade studies of chemokines in renal diseases, [1][2][3][4][5][6][7][8][9][10][11] we focus here on recent developments in pathophysiology of that chemokine effect. CHEMOKINES AND CHEMOKINE RECEPTORSChemokines are a group of chemotactic cytokines (approximately 8 to 17 kD) with the ability to bind G-proteincoupled receptors and act as potent attractants for leukocytes in acute and chronic inflammation. There are four subfamilies of chemokines, including CCL, CXCL, CX3CL, and CL (Figure 1). 7,6 At present, 19 receptors are known ( Figure 1). 6,7 The large CC chemokine family has the first two cysteine residues adjacent to each other, whereas the CXC family has a single amino acid residue in between the first two cysteines. Fractalkine (CX3CL1) is the only member of the CX3C chemokine family where three amino acid residues separate the first two cysteines. Finally, two related chemokines absent the two cysteine residues that bind the XCR1 receptor belong to the XC family. As shown in Figure 1, many chemokines bind multiple receptors and most receptors bind multiple chemokines. However, CC chemokine receptors exclusively bind CC chemokines and CXC receptors bind only CXC chemokines.Chemokines and their corresponding receptors are expressed in different cell types (Figure 2). 7,12 Generally speaking, monocytes are mostly attracted by CCL chemokines acting through CCR1, CCR2, andCCR5receptors,whereasneutrophilsare the target of CXCL chemokines through REGULATION OF CHEMOKINE EXPRESSIONOn the basis of their regulation and production, chemokines can be classified broadly as homeostatic/lymphoid or inflammatory chemokines. The former is responsible for leukocyte homing and ABSTRACTThe main function of chemokines is to guide inflammatory cells in their migration to sites of inflammation. During the last 2 decades, an expanding number of chemokines and their receptors have driven broad inquiry into how inflammatory cells are recruited in a variety of diseases. Although this review focuses on chemokines and their receptors in renal injury, proinflammatory IL-17, TGF␤, and TWEAK signaling pathways also play a critical role in their expression. Recent studies in transgenic mice as well as blockade of chemokine signaling by neutralizing ligands or receptor antagonists now allow direct interrogation of chemokine action. The emerging role of regulatory T cells and Th17 cells during renal injury also forges tight relationships between chemokines and T cell infiltration in the development of kidney disease. As chemokine receptor blockade inches toward clinical use, the field remains an attractive area with potential for unexpected opportunity in the future.

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“…[1][2][3][4] Animal models firmly established ANCA pathogenicity for NCGN. [5][6][7][8][9][10] Numerous in vitro experiments suggest that phagocyte NADPH oxidase (Nox) and granule proteins, including neutrophil serine proteases (NSPs), participate in ANCA-mediated endothelial damage. 2,[11][12][13] We used a murine ANCA NCGN model and recently showed that IL-1b provides an important disease mediator and that proteolytically active NSPs are essential for processing pro-IL-1b to IL1b.…”

mentioning

confidence: 99%

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

Journal of the American Society of Nephrology

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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.

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Th17 Cells Promote Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Cited by 151 publications

References 35 publications

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Chemokines in Renal Injury

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

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