miR-145a Regulation of Pericyte Dysfunction in a Murine Model of Sepsis

J Infect Dis. 2020 Aug 17;222(6):1037-1045. doi: 10.1093/infdis/jiaa184.

Abstract

Background: Sepsis is a life-threatening systemic disease with severe microvascular dysfunction. Pericytes preserve vascular homeostasis. To our knowledge, the potential roles of microRNAs in sepsis-induced pericyte dysfunction have not been explored.

Methods: We determined lung pericyte expression of miR-145a in cecal ligation and puncture (CLP)-induced sepsis. Mouse lung pericytes were isolated and transfected with a miR-145a mimic, followed by stimulation with lipopolysaccharide (LPS). We measured inflammatory cytokine levels. To assess the functions of miR-145a in vivo, we generated a pericyte-specific miR-145a-knockout mouse and determined sepsis-induced organ injury, lung and renal vascular leakage, and mouse survival rates. We used RNA sequencing and Western blotting to analyze the signaling pathways regulated by miR-145a.

Results: CLP led to decreased miR-145a expression in lung pericytes. The miR-145a mimic inhibited LPS-induced increases in cytokines. In CLP-induced sepsis, pericytes lacking miR-145a exhibited increased lung and kidney vascular leakage and reduced survival rates. We found that miR-145a could suppress LPS-induced NF-κB activation. In addition, we confirmed that the transcription factor Friend leukemia virus integration 1 (Fli-1) is a target of miR-145a and that Fli-1 activates NF-κB signaling.

Conclusion: Our results demonstrated that pericyte miR-145a mediates sepsis-associated microvascular dysfunction, potentially by means of Fli-1-mediated modulation of NF-κB signaling.

Keywords: Fli-1; NF-κB; miR-145a; pericytes; sepsis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytokines / blood
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Host-Pathogen Interactions / genetics*
  • Inflammation Mediators / blood
  • Inflammation Mediators / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Models, Biological
  • NF-kappa B / metabolism
  • Pericytes / metabolism*
  • Prognosis
  • RNA Interference
  • Sepsis / etiology*
  • Sepsis / mortality
  • Signal Transduction

Substances

  • Cytokines
  • Inflammation Mediators
  • MIRN145a microRNA, mouse
  • MicroRNAs
  • NF-kappa B