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Abstract: BACKGROUND: The cardiac sympathetic afferent reflex and pulmonary spinal afferent reflex amplify sympathetic activity and may contribute to chronic heart failure. We hypothesized that cardiac injury triggers a cardiac nerve-mediated cytokine uptake cascade that propagates neural inflammation in thoracic dorsal root ganglia (DRGs) and drives reciprocal cardiopulmonary afferent sensitization through suppression of voltage-gated potassium channels after myocardial infarction (MI). METHODS: MI was induced in rats by coronary ligation. Molecular profiling, immunofluorescence, tissue clearing, and functional assays were used to assess neuroinflammation and reflex responses. RESULTS: Post-MI, thoracic DRGs showed macrophage infiltration, glial activation, cytokine upregulation, and reduced voltage-gated potassium channel expression. Bulk RNA-sequencing identified enrichment of macrophage activation-related genes, and in vitro studies confirmed that proinflammatory cytokines and activated macrophages suppressed voltage-gated potassium channels and increased DRG neuron excitability. Epicardial injection of biotinylated TNF-α (tumor necrosis factor-α) demonstrated cardiac afferent-mediated cytokine transport to DRGs, inducing macrophage infiltration via a cytokine receptor-dependent mechanism. Anti-inflammatory interventions, including oral minocycline, systemic macrophage depletion, and local epidural delivery of thermo-responsive hydrogel-forming dexamethasone prodrug (ProGel-Dex), significantly reduced DRG neuroinflammation, restored voltage-gated potassium channel levels, and attenuated exaggerated cardiac sympathetic afferent reflex and pulmonary spinal afferent reflex responses. Minocycline and ProGel-Dex also improved cardiac chamber dilation in the post-MI rats. CONCLUSIONS: These findings identify a neural inflammatory cascade involving cytokine uptake, glial activation, and macrophage activation as a contributor to cardiopulmonary afferent sensitization after MI. Targeting DRG inflammation, particularly with sustained dexamethasone delivery using ProGel-Dex, offers a prospect of precision medicine to dampen pathological sympathetic activation and improve cardiac outcomes in chronic heart failure.