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

Abstract

IL-1β and IL-18 are proinflammatory cytokines that contribute to renal immune complex disease, but whether IL-1β and IL-18 are mediators of intrinsic glomerular inflammation is unknown. In contrast to other cytokines the secretion of IL-1β and IL-18 requires a second stimulus that activates the inflammasome-ASC-caspase-1 pathway to cleave pro-IL-1β 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-1β 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-1β and were able to activate the NLRP3-caspase-1 axis and secrete mature IL-1β. Together, the NLRP3-ASC-caspase-1 axis does not contribute to intrinsic glomerular inflammation via glomerular parenchymal cells as these cannot produce IL-1β during sterile inflammation.

• Authors: Julia Lichtnekert, Onkar P Kulkarni, Shrikant R Mulay, Khader Valli Rupanagudi, Mi Ryu, Ramanjaneyulu Allam, Volker Vielhauer, Dan Muruve, Maja T Lindenmeyer, Clemens D Cohen, Hans-Joachim Anders
• Journal: PloS one (PLoS One) Vol. 6 Issue 10 Pg. e26778 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22046355 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Carrier Proteins
• Cytokines
• Inflammasomes
• Interleukin-1
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• antiglomerular basement membrane antibody
• Caspase 1

Topics

• Animals
• Autoantibodies (immunology)
• Carrier Proteins
• Caspase 1 (metabolism)
• Cytokines
• Enzyme Activation
• Glomerulonephritis (immunology)
• Inflammasomes
• Inflammation
• Interleukin-1 (immunology)
• Interleukin-1beta
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein