Macrophage NLRP3 inflammasome mediates the effects of sympathetic nerve on cardiac remodeling in obese rats

Obesity-associated cardiac remodeling is characterized by cardiac sympathetic nerve over-activation and pro-inflammatory macrophage infiltration. We identified norepinephrine (NE), a sympathetic neurotransmitter, as a pro-inflammatory effector to activate macrophage NLRP3 inflammasome, which contributed to cardiac inflammation. In vivo, Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 12 weeks to establish obese rat models. Obese rats exhibited marked cardiac hypertrophy compared to normal rats. The expression of NLRP3 and interleukin (IL)-1β was upregulated, accompanied by CD68 + NLRP3 + macrophage infiltration in the hearts of the obese rats. The obese rats also showed increased sympathetic nerve activity. β-adrenergic receptor (AR) inhibition mitigated these changes. In vitro, sympathetic neurotransmitter NE significantly exacerbated palmitic acid (PA)-induced macrophage polarization toward pro-inflammatory type and NLRP3 inflammasome activation in THP-1 macrophages. It was further found that the pro-inflammatory role of NE is dependent on the activation of protein kinase A (PKA) and subsequently inhibition of β-arrestin2, which is an important regulator of the nuclear factor-kappa B (NF-κB) pathway. This study identifies the neuro-immune axis as an important mediator in obesity-associated cardiac remodeling. Targeting the neuro-immune system may open therapeutic opportunities for the treatment of cardiac remodeling in obesity. • Obese rats exhibited cardiac hypertrophy, sympathetic nerve over-activation, and increased NLRP3 and IL-1β expression. • Sympathetic nerve activity inhibition alleviated obesity-induced cardiac hypertrophy and pro-inflammatory responses. • Norepinephrine exacerbated palmitic acid-induced macrophage pro-inflammatory polarization and NLRP3 inflammasome activation. • The pro-inflammatory role of norepinephrine is dependent on the PKA-β-arrestin2-NF-κB pathway.