Renal IL-17 expression in human ANCA-associated glomerulonephritis

Velden, Joachim; Paust, Hans‐Joachim; Hoxha, Elion; Turner, Jan-Eric; Steinmetz, Oliver M.; Wolf, Günter; Jabs, Wolfram J.; Özcan, Fedai; Beige, Joachim; Heering, Peter; Schröder, Saskia; Kneissler, U.; Disteldorf, Erik; Mittrücker, Hans‐Willi; Stahl, Rolf A.K.; Helmchen, Udo; Panzer, Ulf

doi:10.1152/ajprenal.00683.2011

Cited by 58 publications

(48 citation statements)

References 41 publications

(48 reference statements)

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“…One recent paper reports that MCs are prominent producers of IL-17 in ANCA-associated GN. 36 These findings are consistent with MCs having an acute injurious role.…”

Section: Discussionsupporting

confidence: 72%

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Gan

O’Sullivan

Ooi

et al. 2015

JASN

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Observations in experimental murine myeloperoxidase (MPO)-ANCA-associated vasculitis (AAV) show mast cells degranulate, thus enhancing injury as well as producing immunomodulatory IL-10. Here we report that, compared with biopsy specimens from control patients, renal biopsy specimens from 44 patients with acute AAV had more mast cells in the interstitium, which correlated with the severity of tubulointerstitial injury. Furthermore, most of the mast cells were degranulated and spindle-shaped in patients with acute AAV, indicating an activated phenotype. We hypothesized that the mast cell stabilizer disodium cromoglycate would attenuate mast cell degranulation without affecting IL-10 production. We induced anti-MPO GN by immunizing mice with MPO and a low dose of anti-glomerular basement membrane antibody. When administered before or after induction of MPO autoimmunity in these mice, disodium cromoglycate attenuated mast cell degranulation, development of autoimmunity, and development of GN, without diminishing IL-10 production. In contrast, administration of disodium cromoglycate to mast cell-deficient mice had no effect on the development of MPO autoimmunity or GN. MPO-specific CD4 + effector T cell proliferation was enhanced by co-culture with mast cells, but in the presence of disodium cromoglycate, proliferation was inhibited and IL-10 production was enhanced. These results indicate that disodium cromoglycate blocks injurious mast cell degranulation specifically without affecting the immunomodulatory role of these cells. Thus as a therapeutic, disodium cromoglycate may substantially enhance the regulatory role of mast cells in MPO-AAV. 27: 132127: -133327: , 201627: . doi: 10.1681 Mast cells (MCs) are best characterized in pathology by their effector roles in IgE-dependent degranulation and by their release of pro-inflammatory mediators in allergy and anaphylaxis. 1 However, it is now recognized that MCs also play important roles in host defense and also in non-allergic inflammatory diseases, particularly those initiated by autoimmunity. The functional diversity of MC phenotypes allows for their participation in the generation of adaptive immune responses, playing either injurious or modulatory roles in many chronic human diseases and animal models of these diseases. 2 A functional role for MCs in a particular human disease can be suspected by confirming MC presence in diseased target organs and demonstrating a correlation between MC activation status and disease outcome. This potential cause and effect association can be strengthened by studies in relevant murine models of the particular diseases comparing disease patterns and outcomes between MC-deficient (Kit Wsh/Wsh ) mice and Kit Wsh/Wsh mice reconstituted with MCs. [2][3][4][5] The mechanistic basis of J Am Soc Nephrol

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“…One recent paper reports that MCs are prominent producers of IL-17 in ANCA-associated GN. 36 These findings are consistent with MCs having an acute injurious role.…”

Section: Discussionsupporting

confidence: 72%

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Gan

O’Sullivan

Ooi

et al. 2015

JASN

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“…Collectively, these data provide evidence in support of both Th1 and Th17 involvement in AAV. Furthermore, IL-17-producing cells were found in renal biopsies from patients with acute vasculitis, and most of the IL-17-positive cells present were innate leukocytes (neutrophils and MCs) (98).…”

Section: Autoimmune Crescentic Glomerulonephritis Lupus Nephritismentioning

confidence: 99%

Cytokines

Holdsworth

Gan

2015

Clinical Journal of the American Society of Nephrology

117

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Cytokines play an important role in host defense against microorganisms. They orchestrate innate immunity by inducing protective local inflammation and systemic acute phase responses. Cytokines are important in initiating, amplifying, directing, mediating, and regulating adaptive immunity. Unfortunately, they may also direct tissue damage if excessive responses occur or if they are involved in directing and mediating autoimmunity. Under these circumstances, cytokines are potential therapeutic targets. Over the last 20 years, we have seen the successful development and clinical implementation of biologic strategies that target key cytokines in specific inflammatory diseases with efficacy, specificity, and toxicity profiles challenging conventional drug therapies. These therapies are finding new applications and many new agents show promise. Unfortunately, these new cytokine-based therapies have had little effect on renal disease. This review provides evidence that common renal diseases, including those causing AKI and the autoimmune proliferative and crescentic forms of GN, have cytokine mediation profiles that suggest they would be susceptible to cytokine-targeting therapeutic strategies.

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“…40 Moreover, the first studies in human ANCA-associated GN suggest a prominent role for T H 17/IL-17 responses in this form of crescentic GN. 4,41 To examine whether our findings are relevant to human disease, we assessed the renal CXCL5 mRNA expression in patients with acute ANCA-associated GN and acute bacterial pyelonephritis, which are both characterized by neutrophil recruitment. In line with the results from our animal models, CXCL5 expression was much higher in renal biopsy specimens from patients with autoimmune-mediated ANCA-associated GN compared with those with acute bacterial pyelonephritis.…”

Section: /2mentioning

confidence: 99%

CXCL5 Drives Neutrophil Recruitment in TH17-Mediated GN

Disteldorf¹,

Krebs²,

Paust³

et al. 2015

Journal of the American Society of Nephrology

Self Cite

112

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Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in T H 17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen-and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic T H 17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in T H 17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens.

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Renal IL-17 expression in human ANCA-associated glomerulonephritis

Cited by 58 publications

References 41 publications

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Cytokines

CXCL5 Drives Neutrophil Recruitment in TH17-Mediated GN

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