Aims Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy. Methods and results A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and β-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient ΔdblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. ΔdblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In ΔdblGATA and wild-type mice, administration of EOS cationic protein mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-β signaling and fibrotic protein synthesis. Use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-β signaling. Conclusion Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of EOS cationic proteins in this human CVD.
Development of abdominal aortic aneurysms (AAA) enhances lesion group‐2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/flIl7rCre/+ mice or induced ILC2 depletion in Icosfl‐DTR‐fl/+Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild‐type (WT) mice, but not ILC2 from Il5−/− mice induces EOS differentiation in bone‐marrow cells from Rorafl/flIl7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5−/− and Il13−/− mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5−/− mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5−/− ILC2 slows AAA growth in Rorafl/flIl7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.
Aims Group 2 innate lymphoid cells (ILC2) regulate adaptive and innate immunities. In mouse heart, production of myocardial infarction (MI) increased ILC2 accumulation, suggesting a role for ILC2 in cardiac dysfunction post-MI. Methods and results We produced MI in ILC2-deficeint Rorafl/flIl7rCre/+ mice and in Icosfl-DTR-fl/+Cd4Cre/+ mice that allowed diphtheria toxin-induced ILC2 depletion. Genetic or induced deficiency of ILC2 in mice exacerbated cardiac dysfunction post-MI injury along with increased myocardial accumulation of neutrophils, CD11b+Ly6Chi monocytes, and CD4+ T cells but deficiency of eosinophils (EOS) and dendritic cells (DC). Post-MI hearts from genetic and induced ILC2-deficient mice contained many more apoptotic cells than those of control mice, and Rorafl/flIl7rCre/+ mice showed thinner and larger infarcts and more collagen-I depositions than the Il7rCre/+ mice only at early time points post-MI. Mechanistic studies revealed elevated blood IL5 in Il7rCre/+ mice at 1, 7, and 28 days post-MI. Such increase was blunted in Rorafl/flIl7rCre/+ mice. Administration of recombinant IL5 reversed EOS losses in Rorafl/flIl7rCre/+ mice, but IL5 did not correct the DC loss in these mice. Adoptive transfer of ILC2, EOS, or DC from wild-type mice, but not ILC2 from Il5–/– mice improved post-MI cardiac functions in Rorafl/flIl7rCre/+ recipient mice. EOS are known to protect cardiomyocytes from apoptosis. Here we showed that DC acted like EOS in blocking cardiomyocyte apoptosis. Yet, ILC2 or IL5 alone did not directly affect cardiomyocyte apoptosis or TGF-β-induced cardiac fibroblast Smad signaling. Conclusion This study revealed an indirect cardiac reparative role of ILC2 in post-MI hearts via the IL5, EOS, and DC mechanism.
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