Header

UZH-Logo

Maintenance Infos

Anti-GBM glomerulonephritis involves IL-1 but is independent of NLRP3/ASC inflammasome-mediated activation of caspase-1


Lichtnekert, J; Kulkarni, O P; Mulay, S R; Rupanagudi, K V; Ryu, M; Allam, R; Vielhauer, V; Muruve, D; Lindenmeyer, M T; Cohen, C D; Anders, H J (2011). Anti-GBM glomerulonephritis involves IL-1 but is independent of NLRP3/ASC inflammasome-mediated activation of caspase-1. PLoS ONE, 6(10):26778.

Abstract

IL-1b and IL-18 are proinflammatory cytokines that contribute to renal immune complex disease, but whether IL-1b and IL-18 are mediators of intrinsic glomerular inflammation is unknown. In contrast to other cytokines the secretion of IL-1b and IL-18 requires a second stimulus that activates the inflammasome-ASC-caspase-1 pathway to cleave pro-IL-1b and -IL-18 into their mature and secretable forms. As the NLRP3 inflammasome and caspase-1 were shown to contribute to postischemic and postobstructive tubulointerstitial inflammation, we hypothesized a similar role for NLRP3, ASC, and caspase-1 in glomerular immunopathology. This concept was supported by the finding that lack of IL-1R1 reduced antiserum-induced focal segmental necrosis, crescent formation, and tubular atrophy when compared to wildtype mice. Lack of IL-18 reduced tubular atrophy only. However, NLRP3-, ASC- or caspase-1-deficiency had no significant effect on renal histopathology or proteinuria of serum nephritis. In vitro studies with mouse glomeruli or mesangial cells, glomerular endothelial cells, and podocytes did not reveal any pro-IL-1b induction upon LPS stimulation and no caspase-1 activation after an additional exposure to the NLRP3 agonist ATP. Only renal dendritic cells, which reside mainly in the tubulointerstitium, expressed pro-IL-1b and were able to activate the NLRP3-caspase-1 axis and secrete mature IL-1b. Together, the NLRP3-ASC-caspase-1 axis does not contribute to intrinsic glomerular inflammation via glomerular parenchymal cells as these cannot produce IL-1b during sterile inflammation.

Abstract

IL-1b and IL-18 are proinflammatory cytokines that contribute to renal immune complex disease, but whether IL-1b and IL-18 are mediators of intrinsic glomerular inflammation is unknown. In contrast to other cytokines the secretion of IL-1b and IL-18 requires a second stimulus that activates the inflammasome-ASC-caspase-1 pathway to cleave pro-IL-1b and -IL-18 into their mature and secretable forms. As the NLRP3 inflammasome and caspase-1 were shown to contribute to postischemic and postobstructive tubulointerstitial inflammation, we hypothesized a similar role for NLRP3, ASC, and caspase-1 in glomerular immunopathology. This concept was supported by the finding that lack of IL-1R1 reduced antiserum-induced focal segmental necrosis, crescent formation, and tubular atrophy when compared to wildtype mice. Lack of IL-18 reduced tubular atrophy only. However, NLRP3-, ASC- or caspase-1-deficiency had no significant effect on renal histopathology or proteinuria of serum nephritis. In vitro studies with mouse glomeruli or mesangial cells, glomerular endothelial cells, and podocytes did not reveal any pro-IL-1b induction upon LPS stimulation and no caspase-1 activation after an additional exposure to the NLRP3 agonist ATP. Only renal dendritic cells, which reside mainly in the tubulointerstitium, expressed pro-IL-1b and were able to activate the NLRP3-caspase-1 axis and secrete mature IL-1b. Together, the NLRP3-ASC-caspase-1 axis does not contribute to intrinsic glomerular inflammation via glomerular parenchymal cells as these cannot produce IL-1b during sterile inflammation.

Statistics

Citations

33 citations in Web of Science®
35 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

101 downloads since deposited on 17 Nov 2011
15 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:17 Nov 2011 10:11
Last Modified:13 Aug 2017 13:32
Publisher:Public Library of Science (PLoS)
ISSN:1932-6203
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.pone.0026778
PubMed ID:22046355

Download

Preview Icon on Download
Preview
Content: Published Version
Filetype: PDF
Size: 2MB
View at publisher
Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)