INTRODUCTION AND AIMS: Interleukin-1β (IL-1β) is an important inflammatory mediator of immune complex-induced glomerulonephritis (GN). As IL-1β
is activated by Caspase 1 in an inflammasome-dependent intracellular process, we examined the functional role of the inflammasome
components Nlrp3 and its adapter molecule Asc in autologous murine nephrotoxic serum nephritis (NTN), a model of immune complex-mediated
GN.
METHODS: NTN was induced in wild-type, Nlrp3- and Asc-deficient C57BL/6 mice after preimmunisation with rabbit IgG. After 21 days
functional parameters (serum urea, total serum protein, serum cholesterol, albuminuria), renal histology and renal leukocyte
infiltrates were compared between the three groups. Moreover, cellular and humoral immune responses against rabbit IgG were
analysed.
RESULTS: In comparison to wild-type, Nlrp3 knockout mice revealed significantly lower serum urea levels and developed a less pronounced
nephrotic syndrome (less hypoproteinemia, hypercholesterolemia, and albuminuria). Consistently, renal leukocyte infiltrates
were significantly decreased in Nlrp3-deficient mice compared to wild-type. The reductions in renal leukocyte counts were
45% for CD45+ leukocytes, 50% for CD4+ T-cells, 40% for CD8+ T-cells, 39% for CD11c+ dendritic cells, and 50% for F4/80+ mononuclear
phagocytes. The reduced accumulation of renal leukocytes correlated with a significantly decreased expression of renal mRNA
for inflammatory chemokines and cytokines like Ccl2, Ccl5, Cxcl10, Ccr6, Tnf, Inf-γ, and IL-1β.
In contrast, NTN was not attenuated in Asc-deficient mice. Functional parameters and leukocyte infiltration were comparable
between Asc knockout mice and wild-type controls.
Analysis of systemic immune responses revealed a decreased cellular activation of Nlrp3-deficient splenocytes after re-stimulation
with rabbit-IgG (reduced surface expression of CD69 on CD4+ T-cells, less secretion of Inf-γ). However, humoral immunity was
exacerbated in Nlrp3-deficient mice, as indicated by increased autologous anti rabbit-IgG serum titers. Asc knockout mice
also demonstrated an attenuated cellular immune response, with humoral immune responses being comparable to those of wild-type
controls.
CONCLUSIONS: In summary, these results identify Nlrp3 as an important pro-inflammatory mediator of immune complex glomerulonephritis.
Surprisingly, we could demonstrate an inflammatory function of Nlrp3 independently of its adapter molecule Asc. Thus, therapeutic
blockade of Nlrp3 receptors, but not Asc may be a new strategy in the treatment of immune complex nephritis.