C Gold (1), V Polewka (1), A Martinez-Navarro (1), L Eivers (1), S Massberg (1), K Stark (1), K Alexander Pekayvaz (1)

1: LMU Klinikum, Medizinische Klinik I, Munich

Resident macrophages and nerves frequently colocalize across diverse tissues, suggesting a spatial and functional relevant relationship. Here, we hypothesized that a sympathetic nerve-driven neuroimmune crosstalk with macrophages might synchronize systemic sympathetic states to local immune programming. We reveal macrophages to particularly colocalize with sympathetic nerves, rather than non-sympathetic nerves. Moreover, macrophages express high levels of β1- and β2-adrenergic receptors, enabling them to detect and respond to norepinephrine, the primary neurotransmitter released by sympathetic nerve fibers. Disruption of this sympathetic nerve–macrophage axis leads to a reorganization of the local macrophage niche. The blockade of sympathetic nerve signalling through systemic or local pharmacological or surgical denervation results in the loss of a distinct 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 modulation 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 through decreased fibronectin degradation. This reveals how chronic sympathetic overactivation translates to local tissue fibrosis through tuning ECM-modulating capacities of the sympathetic nerve associated macrophage niche.