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

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. Method 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 type 2 innate lymphoid 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. Translational perspective Accumulating evidence suggests that modulation of innate and adaptive immune responses is a promising therapeutic strategy for myocardial infarction. In this study, we demonstrate that IL-5 exerts cardioprotective effects on infarcted myocardium by promoting eosinophil accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis. Hence, regulation of cardiac IL-5 level or eosinophil count may become a therapeutic approach for post-myocardial infarction cardiac repair in humans.

Hypereosinophilia causes progressive cardiac pathologies in mice

“…Recently, it has been shown that eosinophil recruitment to the heart is beneficial during myocardial infarction (55)(56)(57). This seems at first contradictory to our findings presented here but it is likely that different mechanisms are at play.…”

Neutrophil membrane-camouflaged nanoparticles alleviate inflammation and promote angiogenesis in ischemic myocardial injury

“…IL-5 has been widely investigated in allergic diseases as a member of the β common chain cytokine family [ 11 , 45 , 46 ]. Recent research suggests that IL-5 improves cardiac function after AMI by modulating local inflammatory conditions [ 16 ]. This therapeutic effect is mainly achieved by increasing the EOS population in the infarcted myocardium.…”

“…Following surgery, all mice were randomized into three groups: PBS (300 μl), NP IL-5 (300 μl), and NM-NP IL-5 (300 μl) (intravenous injection). The total dosage of IL-5 was administrated at 100ug/kg, as described in detail by Xu et al [ 16 ]. Mice were sacrificed on days 3 and 7 for short-term experiments and day 28 for long-term experiments.…”

“…Additionally, Eosinophils (EOS) have been shown to promote tissue repair by secreting various chemokines, cytokines, growth factors, and enzymes [ 13 ], as well as extensive communication with a wide range of cells [ 14 ]. Recently, it has been demonstrated that EOS also exerts cardioprotective properties in infarcted hearts [ 15 , 16 ]. Since IL-5 plays a critical role in the formation, activation, and survival of EOS [ 17 ], we propose that IL-5 can be a promising cardiac detoxification agent during the inflammatory phase in post-MI events.…”

Innate Lymphoid Cells and Myocardial Infarction

“…For the ILC2-related cytokine IL-5, Xu et al. ( 57 ) reported that it facilitates recovery of cardiac function post-MI by promoting eosinophil accumulation and subsequent CD206 + macrophage polarization via the IL-4/STAT6 axis. The ILC2-related cytokine IL-13 could regulate leukocyte recruitment and induce differentiation of M2-like monocytes/macrophages, and could promote recovery of cardiac function after MI by secreting anti-inflammatory cytokines to stimulate new blood vessel formation and collagen deposition, thereby enhancing wound healing in the infarct area ( 26 ).…”