Coronary heart disease remains the leading cause of deaths in the US. Despite the success of lipid lowering, residual risk remains. Recent clinical studies support the role of inflammation in CVD, a longstanding topic of basic research. Group 2 innate lymphoid cells (ILC2) are innate lymphocytes that play essential role in obesity by promoting adipocyte beiging and recruiting beige cells to the white adipose tissue, thereby limiting obesity development. Limited information is available regarding ILC2 function in CVD, although transplantation of bone-marrow from ILC2-deficient mice promoted atherogenesis. Eosinophils (EOS) accumulate in blood or at the site of inflammation after allergic sensitization or parasite infection. Blood EOS count and EOS cationic protein (ECP) levels associate positively with major CV risk factors and CVD prevalence and mortality. Yet other studies reported reduced blood EOS count and ECP levels in patients with major adverse cardiac events and heart failure. Therefore, the role of ILC2 and EOS in human CVD remains unsettled. Our preliminary studies demonstrated ILC2 accumulation in mouse heart after myocardial infarction (MI). ILC2 deficiency (ILC2KO) or diphtheria toxin A (DTA)-induced ILC2 depletion (ILC2DTA) exacerbated cardiac dysfunction, myocardial cell death and fibrosis post-MI. Further study showed that ILC2 deficiency blunted blood IL5, an essential type-2 cytokine from ILC2 that controls the expansion and migration of EOS, dendritic cells (DC), and regulatory T cells (Treg) to the bloodstream or the site of inflammation. FACS analysis revealed deficiency of splenic, blood, or heart EOS and DC in ILC2KO mice post-MI. Administration of mouse recombinant IL5 reversed EOS loss in blood, providing a mechanistic explanation of ILC2 activity in alleviating cardiac dysfunction post-MI and suggesting a concurrent cardioprotective role of EOS and ILC2 in post-MI heart. Consistent with this hypothesis, exacerbated post-MI cardiac dysfunctions in ILC2KO mice got improved after mice receiving adoptive transfer of ILC2 or EOS from wild-type (WT) mice, but not ILC2 from IL5-/- mice. We recently reported high blood EOS count in patients with acute MI and EOS accumulation in mouse heart post- MI. EOS-deficient ∆dblGATA mice (EOSKO) demonstrated exacerbated cardiac dysfunction and myocardial fibrosis, all which can be corrected by repopulation of donor EOS from WT mice or by giving mice recombinant murine EOS cationic protein mEar1 (human ECP ortholog). Similar to the EOSKO mice, DTA-induced depletion of EOS in iPHIL mice (EOSDTA) also worsened the cardiac function post-MI. Based on these observations, we hypothesize that ILC2 protect heart from post-MI cardiac dysfunction. One mechanism is to release type-2 cytokines, such as IL5 to promote the development and migration of bone-marrow EOS to the bloodstream and heart where EOS exert a similar reparative role to that of ILC2 in mitigating ischemic cardiac injury. We propose tw...