Macrophage-Derived CCL24 Promotes Cardiac Fibrosis Via Fibroblast CCR3

Inflammation is a significant risk factor and contributor to the development of cardiovascular disease by driving adaptive and maladaptive responses to cardiac injury. Macrophages are the most abundant immune cells in the heart and play an important role in the remodeling of cardiac tissue. Cardiac resident macrophages (CRMs) are integral components of the myocardium, where they have key roles in inflammation, tissue injury, and remodeling. However, the precise mechanisms by which CRMs regulate remodeling in heart failure remain poorly understood.

We used in vivo and ex vivo approaches to show that CRMs are the primary source of the chemokine CCL24 (C-C motif chemokine ligand 24) in the heart. To investigate the role of CCL24 on cardiac function following pressure overload, we subjected CCL24-deficient mice to transverse aortic constriction. To determine the role of its receptor CCR3 (C-C chemokine receptor type 3) in fibroblast activation, we used CRISPR (clustered regularly interspaced short palindromic repeats) and Cas9 (CRISPR-associated protein 9) to generate fibroblast-specific CCR3-deficient mice. We used cardiac fibroblasts to determine the direct effects of CCL24 and the signaling pathways downstream of CCR3 required for their activation and proliferation.

We identified a subpopulation of CRMs that expresses high levels of CCL24 during pressure overload-induced injury. Following transverse aortic constriction, CCL24 deficiency ameliorated cardiac fibrosis, suggesting a pathological role for CCL24 and revealing that CRMs are a heterogeneous population with dichotomous roles in mediating cardiac remodeling. Mechanistically, CCL24 directly activated cardiac fibroblasts through its sole receptor, CCR3, in an inflammation-independent process. The engagement of the CCR3 receptor promoted fibroblast proliferation and activation via PI3K (phosphoinositide 3-kinase) and the release of the key fibrotic cytokine TGF (transforming growth factor)-β. Following pressure overload, fibroblast-specific deletion of CCR3 improved cardiac function and reduced fibrosis to a degree comparable to that observed in CCL24-deficient mice. Notably, administration of a CCL24-blocking antibody or a CCR3 antagonist enhanced cardiac function in pressure-overloaded mice, underscoring the CCL24-CCR3 axis as a promising therapeutic target for heart failure.

Macrophage-derived CCL24 aggravates fibrosis via the CCR3 receptor, impairing cardiac function in heart failure.