Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion
Shrikant R. Mulay, … , Helen Liapis, Hans-Joachim Anders
Shrikant R. Mulay, … , Helen Liapis, Hans-Joachim Anders
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):236-246. https://doi.org/10.1172/JCI63679.
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Research Article Nephrology

Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion

Abstract

Nephrocalcinosis, acute calcium oxalate (CaOx) nephropathy, and renal stone disease can lead to inflammation and subsequent renal failure, but the underlying pathological mechanisms remain elusive. Other crystallopathies, such as gout, atherosclerosis, and asbestosis, trigger inflammation and tissue remodeling by inducing IL-1β secretion, leading us to hypothesize that CaOx crystals may induce inflammation in a similar manner. In mice, intrarenal CaOx deposition induced tubular damage, cytokine expression, neutrophil recruitment, and renal failure. We found that CaOx crystals activated murine renal DCs to secrete IL-1β through a pathway that included NLRP3, ASC, and caspase-1. Despite a similar amount of crystal deposits, intrarenal inflammation, tubular damage, and renal dysfunction were abrogated in mice deficient in MyD88; NLRP3, ASC, and caspase-1; IL-1R; or IL-18. Nephropathy was attenuated by DC depletion, ATP depletion, or therapeutic IL-1 antagonism. These data demonstrated that CaOx crystals trigger IL-1β–dependent innate immunity via the NLRP3/ASC/caspase-1 axis in intrarenal mononuclear phagocytes and directly damage tubular cells, leading to the release of the NLRP3 agonist ATP. Furthermore, these results suggest that IL-1β blockade may prevent renal damage in nephrocalcinosis.

Authors

Shrikant R. Mulay, Onkar P. Kulkarni, Khader V. Rupanagudi, Adriana Migliorini, Murthy N. Darisipudi, Akosua Vilaysane, Daniel Muruve, Yan Shi, Fay Munro, Helen Liapis, Hans-Joachim Anders

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Figure 1

CaOx crystals activate DCs to secrete mature IL-1β.

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CaOx crystals activate DCs to secrete mature IL-1β. (A) WT BMDCs were st...
(A) WT BMDCs were stimulated with increasing doses of CaOx crystals with or without LPS prestimulation (1 μg/ml), and IL-1β secretion was measured by ELISA. ATP served as a positive control of NLRP3 activation. Western blotting of supernatants showed induction of pro–IL-1β by LPS; only CaOx crystals and ATP induced mature IL-1β secretion. This process involved caspase-1 activation (cleavage product, 10 kDa). (B) DCs from WT, Nlrp3–/–, and Asc–/– mice. CaOx crystal– and ATP-induced IL-1β secretion depended on the presence of NLRP3 and ASC regardless of pro–IL-1β induction. (C) Similar results were obtained in DCs isolated from Casp1–/– mice. (D) WT BMDCs were stimulated with LPS/CaOx with or without the caspase inhibitor Z-VAD-FMK. Data are means ± SD from 3 separate experiments. *P < 0.05 vs. medium; ***P < 0.001 vs. respective WT (B and C) or PBS (D).