Fibroblast growth factor-inducible 14 mediates macrophage infiltration in heart to promote pressure overload-induced cardiac dysfunction

Life Sci. 2020 Apr 15;247:117440. doi: 10.1016/j.lfs.2020.117440. Epub 2020 Feb 15.

Abstract

Aims: Heart failure (HF) is characterized by compromised cardiac structure and function. Previous work has identified a link between upregulation of pro-inflammatory cytokines and HF. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a pro-inflammatory cytokine, which binds to fibroblast growth factor inducible 14 (Fn14), a ubiquitously expressed cell-surface receptor. The objective of this study was to investigate the role of TWEAK/Fn14 pathway in promoting cardiac inflammation under non ischemic stress conditions.

Main methods: Wild type (WT) and Fn14 knock out (Fn14-/-) mice were subjected to pressure overload [transaortic constriction (TAC)] for 1 or 6 weeks. A subset of WT TAC animals were treated with the Fn14 antagonist L524-0366. Cardiac function was measured by echocardiography. Cardiac fibrosis and macrophage infiltration were quantified using immunohistochemistry and flow cytometry, respectively. Cardiac fibroblasts were isolated for quantifying TWEAK-induced chemokine release.

Key findings: Fn14-/- mice displayed improved cardiac function, reduced fibrosis and lower macrophage infiltration in heart compared to WT following TAC. L524-0366 mitigated maladaptive remodeling with TAC. TWEAK induced secretion of the pro-inflammatory chemokine, monocyte chemoattractant protein 1 from WT but not Fn14-/- fibroblasts in vitro, in part through activation of non-canonical NF-κB signaling. Finally, Fn14 expression was increased in mouse following TAC and in human failing hearts.

Significance: Our findings support an important role for the TWEAK/Fn14 promoting macrophage infiltration and fibrosis in heart under non-ischemic stress, with potential for therapeutic intervention to improve cardiac function in the setting of HF.

Keywords: Fn14; Heart failure; Inflammation; MCP-1; NF-κB; Pressure overload induced hypertrophy.

MeSH terms

  • Animals
  • Blood Pressure / physiology*
  • Cell Line
  • Chemokine CCL2 / metabolism
  • Cytokine TWEAK / metabolism
  • Disease Models, Animal
  • Female
  • Fibroblast Growth Factors / metabolism*
  • Heart
  • Heart Failure / metabolism*
  • Humans
  • Inflammation / metabolism
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Signal Transduction
  • TWEAK Receptor / metabolism
  • Tumor Necrosis Factor Inhibitors / metabolism
  • Tumor Necrosis Factor Inhibitors / pharmacology
  • Up-Regulation / drug effects

Substances

  • Chemokine CCL2
  • Cytokine TWEAK
  • NF-kappa B
  • TWEAK Receptor
  • Tumor Necrosis Factor Inhibitors
  • fibroblast growth factor 14
  • Fibroblast Growth Factors