The immunobiology of cardiac macrophages: multifaceted drivers of dysfunction and resolution across the spectrum of heart failure

Abstract

Cardiovascular diseases remain the leading cause of death worldwide. Recent studies have revealed critical roles for inflammation in the onset and progression of heart disease, with macrophages emerging as key immune players in this context. Cardiac macrophages - highly plastic cells with diverse phenotypes - originate from two major sources thatinfluence their functions. Cardiac resident macrophages (CRMs) arise from embryonic progenitors and populate the heart during development, while monocyte-derived macrophages (MoMFs) are recruited from the bone marrow in response to injury. MoMFs typically mediate inflammatory responses and contribute to tissue damage, whereas CRMs are generally anti-inflammatory and play protective roles in both homeostasis and disease. However, CRMs are a heterogeneous population comprising multiple subtypes with distinct genetic signatures that influence their function across various disease states. This thesis investigates how macrophage heterogeneity, arising both from their origin and microenvironment, relates to their functional roles. Using both acute and chronic injury models, I examine the diverse roles of cardiac macrophages in modulating disease outcomes, with a specific focus on their bidirectional influence. In a model of acute pressure overload, I define CRM contributions to both fibrosis and angiogenesis. While overall a protective cell population, I identify a subset of CRMs that can aggravate fibrosis through the release of Chemokine (C-C motif) ligand 24 (CCL24). Finally, I characterize a specialized subset of cardiac macrophages known as lipid-associated macrophages (LAMs), which exhibit conserved genetic features across tissues and play a role in modulating disease in obesity- and hypertension-associated heart failure. Together, these studies highlight the functional duality and context-specific behavior of macrophages in cardiac pathology. This thesis underscores the importance of dissecting macrophage heterogeneity to inform targeted therapeutic strategies for heart failure.