Background <p>Inflammation and the nervous system play pivotal roles in cardiac remodeling after myocardial infarction (MI). Recent study showed renal denervation (RDN) could reduce cardiac inflammation, however, the specific mechanism remains unclear.</p> Methods <p>We firstly reanalyzed the previous heart single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to examine the alterations in immune cell subsets following MI. Subsequently, we carried out diverse denervation procedures to explore the relationship between the nerve axis and the inflammatory response. Finally, we performed bulk RNA-seq and neurotransmitter analysis to explore the molecular mechanisms implicated in the migration of splenic myeloid cells after MI.</p> Results <p>Myeloid cells manifested the most substantial changes following MI and accumulated in the vicinity of the infarct area. The afferent renal nerve - splenic nerve axis regulates the migratory capacities of splenic myeloid cells after MI. RDN decreased the norepinephrine (NE) levels in the spleen after MI and attenuated the expression of ITGA9 on splenic myeloid cells, which impaired their interaction with VCAM-1 on cardiac endothelial cells and thereby reduced their migration to the heart.</p> Conclusions <p>Our study highlights the crucial role of the afferent renal nerve-splenic nerve axis in regulating cardiac inflammation and provides a interventional target for improving cardiac function after myocardial ischemic injury.</p>