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.