Interleukin-5-induced eosinophil population improves cardiac function after myocardial infarction

Cardiovasc Res. 2022 Jul 20;118(9):2165-2178. doi: 10.1093/cvr/cvab237.

Abstract

Aims: Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms.

Methods and results: MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and CD127+ cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation.

Conclusion: IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis.

Keywords: Alternatively activated macrophage; Eosinophil; Interleukin-4; Interleukin-5; Myocardial infarction.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Eosinophils* / metabolism
  • Interleukin-4 / metabolism
  • Interleukin-5* / metabolism
  • Interleukin-5* / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction* / metabolism
  • Myocardial Infarction* / therapy
  • Myocardium* / metabolism
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction
  • Ventricular Remodeling / physiology

Substances

  • Il4 protein, mouse
  • Interleukin-5
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Interleukin-4