Neural Inflammation in Thoracic Dorsal Root Ganglia Mediates Cardiopulmonary Spinal Afferent Sensitization in Chronic...

The cardiac sympathetic afferent reflex (CSAR) and pulmonary spinal afferent reflex (PSAR) amplify sympathetic activity and may contribute to chronic heart failure (CHF). We hypothesized that neural inflammation in thoracic dorsal root ganglia (DRGs) drives cardiopulmonary afferent sensitization through suppression of voltage-gated potassium (Kv) channels after myocardial infarction (MI). MI was induced in rats by coronary ligation. Molecular profiling, immunofluorescence, tissue clearing, and functional assays were used to assess neuroinflammation and reflex responses. Post-MI, thoracic DRGs showed macrophage infiltration, glial activation, cytokine upregulation, and reduced Kv channel expression. Bulk RNA-seq identified enrichment of macrophage activation-related genes, and in vitro studies confirmed that pro-inflammatory cytokines and activated macrophages suppressed Kv channels and increased DRG neuron excitability. Epicardial injection of biotinylated TNF-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 Kv channel levels, and attenuated exaggerated CSAR and PSAR responses. ProGel-Dex also improved cardiac chamber dilation in the post-MI rats. These findings identify a cytokine uptake-glial activation-macrophage activation pathway as a driver of cardiopulmonary afferent sensitization after MI. Targeting DRG inflammation, particularly with sustained local dexamethasone delivery using ProGel-Dex, offers a precision medicine to dampen pathological sympathetic activation and improve cardiac outcomes in CHF.