CCR5 signaling promotes lipopolysaccharide-induced macrophage recruitment and alveolar developmental arrest

Cell Death Dis. 2021 Feb 15;12(2):184. doi: 10.1038/s41419-021-03464-7.

Abstract

The pathogenesis of bronchopulmonary dysplasia (BPD), involves inflammatory, mechanisms that are not fully characterized. Here we report that overexpression of C-C chemokine receptor 5 (CCR5) and its ligands is associated with BPD development. Lipopolysaccharide-induced BPD rats have increased CCR5 and interleukin-1β (IL-1β) levels, and decreased alveolarization, while CCR5 or IL-1β receptor antagonist treatments decreased inflammation and increased alveolarization. CCR5 enhances macrophage migration, macrophage infiltration in the lungs, IL-1β levels, lysyl oxidase activity, and alveolar development arrest. CCR5 expression on monocytes, and its ligands in blood samples from BPD infants, are elevated. Furthermore, batyl alcohol supplementation reduced CCR5 expression and IL-1β production in lipopolysaccharide-exposed rat lungs. Moreover, receptor-interacting kinase 3 (RIP3) upstream regulator of CCR5-cultured RIP3-/- macrophages exhibited partly blocked lipopolysaccharide-induced CCR5 expression. We conclude that increased CCR5 expression is a key mechanism in BPD development and represents a novel therapeutic target for treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism
  • Animals
  • Bronchopulmonary Dysplasia / metabolism
  • Cell Movement / physiology
  • Disease Models, Animal
  • Female
  • Humans
  • Interleukin-1beta / biosynthesis
  • Lipopolysaccharides / pharmacology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / metabolism*
  • Mice
  • Mice, Knockout
  • Pregnancy
  • RAW 264.7 Cells
  • Rats
  • Rats, Sprague-Dawley
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Receptors, CCR5 / metabolism*
  • Signal Transduction
  • Up-Regulation

Substances

  • CCR5 protein, human
  • CCR5 protein, mouse
  • Interleukin-1beta
  • Lipopolysaccharides
  • Receptors, CCR5
  • Receptor-Interacting Protein Serine-Threonine Kinases