An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice.
Intrarenal crystal formation activates the Nlrp3 inflammasome in myeloid cells and triggers a profound inflammatory response. Here, we studied whether a specific inhibitor of the Nlrp3 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 (IL)-1β 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-1β-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.
Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Isis
I
Ludwig-Portugall
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany; Institute of Molecular Medicine, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Eva
E
Bartok
Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Ermanila
E
Dhana
Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Beatrix D G
BD
Evers
Institute of Innate Immunity, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Michael J
MJ
Primiano
Institute of Innate Immunity, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
J Perry
JP
Hall
Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA.
Bernardo S
BS
Franklin
Institute of Molecular Immunology, Technische Universität München, Munich, Germany.
Percy A
PA
Knolle
Institute of Molecular Medicine, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Veit
V
Hornung
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Gunther
G
Hartmann
Department of Nephrology, University of Aachen, Aachen, Germany.
Peter
P
Boor
Institute of Innate Immunity, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany; Inflammation and Immunology Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Eicke
E
Latz
Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany. Electronic address: ckurts@web.de.
Christian
C
Kurts
D000225:Adenine / Q000009:adverse effects; D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007192:Indenes; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D009393:Nephritis / Q000139:chemically induced / Q000188:drug therapy*; D010070:Oxalates / Q000009:adverse effects; D061251:Primary Cell Culture; D015398:Signal Transduction; D013449:Sulfonamides; D013450:Sulfones / Q000627:therapeutic use*
D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; C587672:IL1B protein, mouse; D007192:Indenes; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010070:Oxalates; D013449:Sulfonamides; D013450:Sulfones; C000597426:N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide; D000225:Adenine
cytokines; dendritic cells; fibrosis; imaging; inflammasome