Monday, May 17, 2021
5/17/2021
Macrophage expansion in the failing heart induces tissue injury and is thought to contribute to the progression of heart failure (HF). The main contributors to macrophage expansion in the failing heart are cells that self-renew and proliferate independent of the blood monocyte pool (and hence are C-C chemokine receptor 2 [CCR2]–). However, the role of such locally-sourced macrophages in the pathogenesis of chronic left ventricular (LV) remodeling is poorly understood. The normal heart harbors macrophages expressing CD206 (Mrc1), along with the gene markers Ym1, Fizz1, and Arg1, that are primarily CCR2–. These CD206+ macrophages can be activated by Th2 cytokines such as interleukin(IL)-4/IL-13. Moreover, secreted FIZZ1 contributes to myofibroblast activation and fibrosis in other disease models. Our pilot data indicate that CD206+ macrophages expressing IL- 4 receptora (IL-4Ra) robustly increase in the failing heart, and suggest that macrophage IL-4/IL-4Ra signaling promotes LV remodeling and fibrosis, in part through FIZZ1. Hence, we hypothesize that cardiac CD206+ macrophages expressing IL-4Ra and Fizz1 are innate immune mediators of adverse LV remodeling in chronic HF, and key targets for therapeutic immunomodulation. Three Aims will test this hypothesis. In Aim 1, in a murine coronary ligation model, using flow cytometry, cell sorting, single cell RNA sequencing (scRNAseq), and immunohistochemistry, we will comprehensively define pathological alterations in cardiac CD206+ macrophages in HF, including IL-4Ra levels and downstream signaling, FIZZ1 expression, and in vivo cell abundance, proliferation, turnover and phagocytic capacity. Using scRNAseq, we will define novel functional subpopulations of CD206+ macrophages at the transcriptional level in both murine and human failing hearts. In Aim 2, we will establish the pathogenetic role of CD206+IL-4Ra+ macrophages in HF using CD45.2 inducible myeloid-specific IL-4Ra knockout mice, deleting myeloid IL-4Ra during chronic HF, and assessing the late effects on LV remodeling, inflammation, and fibrosis. To establish sufficiency of failing heart CD206+IL-4Ra+ macrophages to induce tissue injury, we will adoptively transfer sorted cardiac CD206+ macrophages with intact or deleted IL- 4Ra from HF mice into naïve CD45.1 mice via intramyocardial injection and assess LV remodeling 6 w later. To assess the role of FIZZ1, we will similarly transfer M[IL-4] polarized bone marrow macrophages from wild-type and Fizz1-/- mice. In Aim 3, we will test potentially translatable therapies to antagonize CD206+IL-4Ra+ macrophages and alleviate chronic LV remodeling, including systemic anti-sense oligonucleotides against IL- 4Ra and Fizz1, anti-IL-4 neutralizing antibody, and GW2580, a small molecule cFMS kinase inhibitor. We will measure the effects of these therapies on LV remodeling, cardiac macrophages, fibrosis, and chemokine/ cytokine expression. These studies will further our understanding of the innate immune basis for cardiac inflammation in ischemic HF, provide novel insights into macrophage IL-4-dependent signaling and Fizz1 in the pathogenesis of LV remodeling, and identify new approaches for cell type-specific immunomodulation in HF.
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