Group 2 innate lymphoid cells protect mouse heart from myocardial infarction injury via interleukin 5, eosinophils, and dendritic cells

Aims Group 2 innate lymphoid cells (ILC2s) 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 Rora(f)(l/fl)Il7r(Cre/)(+) mice and in lcos(fl-DTR-fl/+)Cd4(Cre/+) 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(+)Ly6C(hi) 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 Rora(f)(l/fl)Il7r(Cre/)(+) mice showed thinner and larger infarcts and more collagen-I depositions than the Il7r(Cre/+) mice only at early time points post-MI. Mechanistic studies revealed elevated blood 1L5 in Il7r(Cre/+) mice at 1, 7, and 28 days post-MI. Such increase was blunted in Rora(f)(l/fl)Il7r(Cre/)(+) mice. Administration of recombinant IL5 reversed EOS losses in Rora(f)(l/fl)Il7r(Cre/)(+) 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 Rora(f)(l/fl)Il7r(Cre/)(+) 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-beta (transforming growth factor-beta)-induced cardiac fibroblast Smad signalling. Conclusion This study revealed an indirect cardiac reparative role of ILC2 in post-MI hearts via the IL5, EOS, and DC mechanism. [GRAPHICS] .