Early activation of the cardiac CX3CL1/CX3CR1 axis delays β-adrenergic-induced heart failure

We recently highlighted a novel potential protective paracrine role of cardiac myeloid CD11b/c cells improving resistance of adult hypertrophied cardiomyocytes to oxidative stress and potentially delaying evolution towards heart failure (HF) in response to early beta-adrenergic stimulation. Here we characterized macrophages (M phi) in hearts early infused with isoproterenol as compared to control and failing hearts and evaluated the role of upregulated CX3CL1 in cardiac remodeling. Flow cytometry, immunohistology and M phi-depletion experiments evidenced a transient increase in M phi number in isoproterenol-infused hearts, proportional to early concentric hypertrophy (ECH) remodeling and limiting HF. Combining transcriptomic and secretomic approaches we characterized M phi-enriched CD45(+) cells from ECH hearts as CX3CL1- and TNF alpha-secreting cells. In-vivo experiments, using intramyocardial injection in ECH hearts of either Cx3cl1 or Cx3cr1 siRNA, or Cx3cr1(-/-) knockout mice, identified the CX3CL1/CX3CR1 axis as a protective pathway delaying transition to HF. In-vitro results showed that CX3CL1 not only enhanced ECH M phi proliferation and expansion but also supported adult cardiomyocyte hypertrophy via a synergistic action with TNF alpha. Our data underscore the in-vivo transient protective role of the CX3CL1/CX3CR1 axis in ECH remodeling and suggest the participation of CX3CL1-secreting M phi and their crosstalk with CX3CR1-expressing cardiomyocytes to delay HF.

Automated summary

The study reveals a transient protective role of the CX3CL1/CX3CR1 axis in early cardiac hypertrophy remodeling, delaying the transition to heart failure by interactions between MΦ and cardiomyocytes.