Journal
KIDNEY INTERNATIONAL
Volume 90, Issue 3, Pages 525-539Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2016.03.035
Keywords
cytokines; dendritic cells; fibrosis; imaging; inflammasome
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFBTR57, BO 3755/2-1, SFB704]
- Excellence Cluster ImmunoSensation
- German Federal Ministry of Education and Research [BMBF 01GM1518A]
- BONFOR internal research support program of the University Clinic of Bonn
- German Research Foundation
- flow-cytometry core facility
- House for Experimental Therapy
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Intrarenal crystal formation activates the NIrp3 inflammasome in myeloid cells and triggers a profound inflammatory response. Here, we studied whether a specific inhibitor of the NIrp3 inflammasome, CP-456,773, can prevent kidney fibrosis in a murine model of crystal nephropathy induced by diets rich in oxalate or adenine. Inflammasome activation in renal dendritic cells and the resulting interleukin (1)-1 beta and IL-18 production were markedly reduced by CP-456,773 treatment both ex vivo and in vivo. We directly visualized intrarenal inflammasome activation and its inhibition by CP-456,773 in vivo by adoptive transfer of bone marrow cells transduced with interleukin-1 beta-Gaussia luciferase, a proteolytic luciferase-based reporter for inflammasome activation, into irradiated mice. CP-456,773 treatment strongly attenuated kidney fibrosis when given early in the genesis of crystal nephropathy, but was unable to reverse established crystal-induced fibrosis. The urinary IL-18 concentration appeared to be a useful noninvasive biomarker for renal inflammasome activation. Finally, NLRP3 inhibition did not compromise adaptive immune responses as previously reported for the global inhibition of IL-1 signaling. Thus, early NLRP3 inhibition by CP-456,773 may be an effective treatment for crystal nephropathy. Use of iGLuc transfected cells introduces a novel imaging technique for inflammasome activation in mice.
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