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

Summary The cardiac sympathetic afferent reflex (CSAR) and pulmonary spinal afferent reflex (PSAR) amplify sympathetic outflow, and their sensitization contributes to chronic heart failure (CHF). Using a myocardial infarction (MI) rat model, molecular profiling, imaging, and functional assays revealed that thoracic dorsal root ganglia (DRGs) undergo marked macrophage and glial activation and suppression of voltage-gated potassium (Kv) channels after MI. In vitro studies confirmed that pro-inflammatory cytokines and activated macrophages directly reduce Kv channel expression and activity in DRG neurons. Cardiac afferents mediated cytokine transport from the heart to DRGs, driving macrophage infiltration in a cytokine receptor-dependent manner. Anti-inflammatory strategies including systemic minocycline, liposomal clodronate–induced macrophage depletion, or local epidural dexamethasone prodrug delivery reduced neuroinflammation, restored Kv channel levels, attenuated the exaggerated CSAR and PSAR, and improved cardiac remodeling. These findings highlight a cytokine uptake–driven inflammatory pathway in cardiopulmonary spinal afferent sensitization and support targeted DRG anti-inflammatory therapy as a potential cardioprotective approach. Abstract 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. Highlights Both cardiac (CSAR) and pulmonary (PSAR) spinal afferent reflexes are sensitized after myocardial infarction, contributing to sympathetic overactivation. Thoracic dorsal root ganglia (T1–T4) exhibit macrophage activation, glial responses, pro- inflammatory cytokine upregulation, and suppression of Kv channels following MI. Cardiac afferents mediate receptor-dependent uptake and transport of cytokines (e.g., TNF-α) from the heart to DRGs, driving macrophage infiltration and inflammation. Activated macrophages and pro-inflammatory cytokines reduce Kv channel expression and Kv current density (Ito) in DRG neurons, enhancing excitability. Anti-inflammatory strategies including minocycline, liposomal clodronate–induced macrophage depletion, and local epidural dexamethasone prodrug attenuate neuroinflammation, restore Kv channel expression, and suppress exaggerated CSAR/PSAR. Targeting DRG inflammation, particularly via sustained epidural dexamethasone delivery, represents a promising cardioprotective precise medicine.