Abstract 14035: IL-4Ra-Mediated CD206 + Macrophage Activation Promotes Adverse Remodeling in the Failing Heart

Abstract

Background: In heart failure (HF), cardiac macrophages are largely comprised of CD206 + cells that locally self-renew independent of the blood monocyte pool. We tested the hypothesis that cardiac CD206 + macrophages expressing interleukin (IL)-4Rα are key mediators of adverse left ventricular (LV) remodeling in HF. Methods and Results: Adult male C57BL/6 mice underwent non-reperfused myocardial infarction (MI) to induce HF. HF mice (vs. sham mice) exhibited progressive expansion of cardiac CD206 + macrophages up to 8 w post-MI (accounting for ~80% total macrophages), whereas cardiac CD206 - macrophages peaked at 48 h and then decreased by 90% at 1 w post-MI and beyond. Cardiac CD206 + macrophage levels negatively correlated with LV ejection fraction, and positively correlated with remote zone fibrosis. These cells were predominantly CCR2 - and nearly half expressed IL-4Rα, whereas CD206 - macrophages, monocytes, neutrophils, and T-cells had markedly lower IL-4Rα expression. Bone marrow-derived macrophages (BMDMs) polarized with IL-4 (M[IL-4]) induced myofibroblast activation in vitro . Intramyocardial adoptive transfer of M[IL-4] macrophages (1 x 10 6 cells) into naïve mice induced progressive LV chamber dilation and dysfunction, and augmented cardiac fibrosis over 4 w. Next, sham and HF mice with similar LV remodeling at 4 w post-MI were given IL-4Rα-specific or control antisense oligonucleotides (ASOs) 40 mg/kg i.p. every 3 d for 4 w. HF mice receiving IL-4Rα ASOs exhibited profoundly diminished cardiac CD206 + IL-4Rα + (and total CD206 + ) macrophage levels, substantially less macrophage proliferation and phagocytosis, and improvement of LV dysfunction, hypertrophy, and fibrosis. Moreover, both M[IL-4] CD206 + BMDMs and CD206 + IL-4Rα + macrophages in failing hearts expressed high levels of Fizz1 (found in inflammatory zone 1). Blocking FIZZ1 expression and/or secretion blunted the profibrotic capacity of M[IL-4] CD206 + BMDMs in vitro . Conclusion: CD206 + IL-4Rα + macrophages proliferate and expand in the failing heart and are key drivers of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206 + macrophage IL-4Rα signaling may be a fruitful therapeutic approach for alleviating LV remodeling in HF.