Peptidylarginine deiminase 4 promotes age-related organ fibrosis

J Exp Med. 2017 Feb;214(2):439-458. doi: 10.1084/jem.20160530. Epub 2016 Dec 28.

Abstract

Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4-/- mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4-/- mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4-/- myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.

MeSH terms

  • Age Factors
  • Animals
  • Collagen / metabolism
  • Extracellular Traps / physiology
  • Fibrosis
  • Hydrolases / genetics
  • Hydrolases / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / pathology*
  • Protein-Arginine Deiminase Type 4
  • Pulmonary Fibrosis / etiology
  • Reactive Oxygen Species / metabolism
  • Ventricular Function, Left

Substances

  • Reactive Oxygen Species
  • Collagen
  • Hydrolases
  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse