Knockout of the interleukin-36 receptor protects against renal ischemia-reperfusion injury by reduction of proinflammatory cytokines

Kidney Int. 2018 Mar;93(3):599-614. doi: 10.1016/j.kint.2017.09.017. Epub 2017 Dec 11.

Abstract

IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL-36α, IL-36β, and IL-36γ, all of which bind to a heterodimer containing the IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. Therefore, we evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury model of AKI using IL-36R knockout and wild-type mice. IL-36R was found to be expressed in the kidney, mainly in proximal tubules. In IL-36R knockout mice, plasma creatinine, blood urea nitrogen, and IL-6 levels after ischemia-reperfusion injury were significantly lower than those in wild-type mice. Immunohistological analysis revealed mild tubular injury. IL-36α/β/γ levels were increased after ischemia-reperfusion injury, and IL-36α was expressed in lymphocytes and proximal tubular cells, but post-ischemia-reperfusion injury mRNA levels of IL-6 and TNF-α were low in IL-36R knockout mice. In primary cultures of renal tubular epithelial cells, IL-36α treatment upregulated NF-κB activity and Erk phosphorylation. Notably, in patients with AKI, urine IL-36α levels were increased, and IL-36α staining in renal biopsy samples was enhanced. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI.

Keywords: IL-36; IL-36 receptor; acute kidney injury; cytokine; ischemia-reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Down-Regulation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Genetic Predisposition to Disease
  • Humans
  • Inflammation Mediators / metabolism*
  • Interleukin-1 / metabolism
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Phenotype
  • Phosphorylation
  • Receptors, Interleukin-1 / deficiency*
  • Receptors, Interleukin-1 / genetics
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Signal Transduction

Substances

  • Cytokines
  • IL36A protein, human
  • Inflammation Mediators
  • Interleukin-1
  • NF-kappa B
  • Receptors, Interleukin-1
  • interleukin-36 receptor, mouse
  • Extracellular Signal-Regulated MAP Kinases