An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice

Kidney Int. 2016 Sep;90(3):525-39. doi: 10.1016/j.kint.2016.03.035. Epub 2016 Jun 2.

Abstract

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.

Keywords: cytokines; dendritic cells; fibrosis; imaging; inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / adverse effects
  • Adoptive Transfer
  • Animals
  • Cells, Cultured
  • Dendritic Cells / metabolism*
  • Disease Models, Animal
  • Fibrosis
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use*
  • Humans
  • Immunohistochemistry
  • Inflammasomes / drug effects*
  • Inflammasomes / metabolism
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Kidney / cytology
  • Kidney / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • Nephritis / chemically induced
  • Nephritis / drug therapy*
  • Oxalates / adverse effects
  • Primary Cell Culture
  • Signal Transduction
  • Sulfones / therapeutic use*

Substances

  • Heterocyclic Compounds, 4 or More Rings
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • MCC-950
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Oxalates
  • Sulfones
  • Adenine