The sympathetic nervous system exerts powerful control over cardiovascular homeostasis, yet the mechanisms linking chronic sympathetic activation to myocardial fibrosis remain incompletely defined. Here, we hypothesized that a sympathetic nerve-driven neuroimmune crosstalk with macrophages synchronizes systemic sympathetic states to local immune programming, forming a distinct spatially and functionally relevant unit. We reveal that macrophages colocalize with sympathetic, rather than non-sympathetic, nerves and respond to norepinephrine - the primary neurotransmitter released by sympathetic fibers - via β1- and β2-adrenergic signalling. Disruption of this sympathetic nerve–macrophage axis through surgical denervation results in the loss of a distinct proinflammatory macrophage niche associated with sympathetic nerves. Furthermore, disruption of β1- and β2-adrenergic signalling fosters a profound shift in macrophage phenotype and alters macrophage function, particularly macrophage mediated regulation of extracellular matrix. Consistently, employing an in vivo model featuring macrophage-specific deletion of adrenergic receptors during chronic progressive cardiovascular fibrosis, we show that loss of β1- and β2-adrenergic signalling leads to a decrease of cardiac fibrosis. This reveals how chronic sympathetic overactivation translates to myocardial fibrosis through tuning ECM-regulating capacities of the sympathetic nerve associated macrophage niche.
