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

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.