The angiocrine Rspondin3 instructs interstitial macrophage transition via metabolic-epigenetic reprogramming and resolves inflammatory injury

Nat Immunol. 2020 Nov;21(11):1430-1443. doi: 10.1038/s41590-020-0764-8. Epub 2020 Aug 24.

Abstract

Macrophages demonstrate remarkable plasticity that is essential for host defense and tissue repair. The tissue niche imprints macrophage identity, phenotype and function. The role of vascular endothelial signals in tailoring the phenotype and function of tissue macrophages remains unknown. The lung is a highly vascularized organ and replete with a large population of resident macrophages. We found that, in response to inflammatory injury, lung endothelial cells release the Wnt signaling modulator Rspondin3, which activates β-catenin signaling in lung interstitial macrophages and increases mitochondrial respiration by glutaminolysis. The generated tricarboxylic acid cycle intermediate α-ketoglutarate, in turn, serves as the cofactor for the epigenetic regulator TET2 to catalyze DNA hydroxymethylation. Notably, endothelial-specific deletion of Rspondin3 prevented the formation of anti-inflammatory interstitial macrophages in endotoxemic mice and induced unchecked severe inflammatory injury. Thus, the angiocrine-metabolic-epigenetic signaling axis specified by the endothelium is essential for reprogramming interstitial macrophages and dampening inflammatory injury.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers
  • Cellular Reprogramming* / genetics
  • Cellular Reprogramming* / immunology
  • Disease Models, Animal
  • Disease Susceptibility
  • Energy Metabolism*
  • Epigenesis, Genetic*
  • Fluorescent Antibody Technique
  • Inflammation / etiology*
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Thrombospondins / genetics*
  • Thrombospondins / metabolism

Substances

  • Biomarkers
  • R-spondin3 protein, mouse
  • Thrombospondins