IL-15 Prevents Renal Fibrosis by Inhibiting Collagen Synthesis: A New Pathway in Chronic Kidney Disease?

Int J Mol Sci. 2021 Oct 28;22(21):11698. doi: 10.3390/ijms222111698.

Abstract

Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end-stage kidney disease. Recently, interleukin-15 (IL-15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL-15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL-15's renoprotective role by pharmologically delivering IL-15 coupled or not with its soluble receptor IL-15Rα. Despite the lack of effects on myofibroblast accumulation, both IL-15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL-15 treatments inhibited collagen and fibronectin secretion by transforming growth factor-β (TGF-β)-treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL-15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL-15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL-15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL-15 may represent a new therapeutic option for CKD.

Keywords: chronic kidney disease; extracellular matrix; fibrosis; interleukin-15; myofibroblasts; unilateral ureteral obstruction.

MeSH terms

  • Animals
  • Chemokine CCL2 / metabolism
  • Collagen / biosynthesis
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Humans
  • Interleukin-15 / metabolism
  • Interleukin-15 / pharmacology
  • Interleukin-15 / therapeutic use*
  • Interleukin-15 Receptor alpha Subunit / metabolism
  • Interleukin-15 Receptor alpha Subunit / therapeutic use*
  • Kidney / metabolism*
  • Kidney / pathology
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Nephrosclerosis / prevention & control*
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / metabolism
  • Ureteral Obstruction

Substances

  • Chemokine CCL2
  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Collagen