• J. Immunol. · Feb 2013

    Inflammasome-independent NLRP3 augments TGF-β signaling in kidney epithelium.

    • Wenjie Wang, Xiangyu Wang, Justin Chun, Akosua Vilaysane, Sharon Clark, Gabrielle French, Nathan A Bracey, Kiril Trpkov, Shirin Bonni, Henry J Duff, Paul L Beck, and Daniel A Muruve.
    • Department of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
    • J. Immunol. 2013 Feb 1; 190 (3): 1239-49.

    AbstractTubulointerstitial inflammation and fibrosis are strongly associated with the outcome of chronic kidney disease. We recently demonstrated that the NOD-like receptor, pyrin domain containing-3 (NLRP3) contributes to renal inflammation, injury, and fibrosis following unilateral ureteric obstruction in mice. NLRP3 expression in renal tubular epithelial cells (TECs) was found to be an important component of experimental disease pathogenesis, although the biology of NLRP3 in epithelial cells is unknown. In human and mouse primary renal TECs, NLRP3 expression was increased in response to TGF-β1 stimulation and associated with epithelial-mesenchymal transition (EMT) and the expression of α-smooth muscle actin (αSMA) and matrix metalloproteinase (MMP) 9. TGF-β1-induced EMT and the induction of MMP-9 and αSMA were significantly decreased in mouse Nlrp3(-/-) renal TECs, suggesting a role for Nlrp3 in TGF-β-dependent signaling. Although apoptosis-associated speck-like protein containing a CARD domain(-/-) TECs demonstrated a phenotype similar to that of Nlrp3(-/-) cells in response to TGF-β1, the effect of Nlrp3 on MMP-9 and αSMA expression was inflammasome independent, as IL-1β, IL-18, MyD88, and caspase-1 were dispensable. Smad2 and Smad3 phosphorylation in response to TGF-β1 was attenuated in Nlrp3(-/-) and apoptosis-associated speck-like protein containing a CARD domain(-/-) cells, accounting for the dampened EMT and TGF-β1 responsiveness in these cells. Consistent with these findings, overexpression of NLRP3 in 293T cells resulted in increased Smad3 phosphorylation and activity. Taken together, these data support a novel and direct role for NLRP3 in promoting TGF-β signaling and R-Smad activation in epithelial cells independent of the inflammasome.

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