Knockdown of Interleukin 17 Receptor A (IL‐17RA) in Paraventricular Nucleus of Hypothalamus Attenuates IL‐17‐induced Pressor Responses and Sympathetic Excitation

Abstract

Inflammation contributes significantly to cardiovascular and autonomic dysfunction in hypertension and heart failure. Over the years, the pro‐inflammatory cytokine interleukin (IL)‐17 (also known as IL‐17A) has been recognized as a critical inflammatory regulator bridging immune responses and tissue inflammation. Our previous studies have demonstrated that peripherally or centrally administrated IL‐17A dramatically elevates blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in rats, and that its receptors IL‐17RA are richly expressed in the brain. The present work sought to determine whether IL‐17RA in the hypothalamic paraventricular nucleus (PVN), a key cardiovascular/autonomic brain center, mediate hemodynamic and sympathetic responses to systemically administered IL‐17A. In urethane anesthetized male SD rats, Mean BP (MBP, mmHg), HR (beats/min) and RSNA (% change) were recorded before and for 6–8 hours after an intravenous (IV) injection of IL‐17A (500 ng). In age‐matched control rats, IV IL‐17A induced a large and long‐lasting increase (*p<0.001 vs. baseline) in MBP (16.2 ± 2.3*), HR (49.8 ± 5.1*) and RSNA (165.6 ± 13.2 %*), beginning within 120 mins and peaking 6–8 hours after the injection. However, in rats pretreated with bilateral PVN microinjections of an IL‐17RA siRNA AAV virus and studied one week later, the IV IL‐17A‐elicited pressor responses in MBP (10.1 ± 2.1*), HR (22.1 ± 4.0*) and RSNA (68.5 ± 7.8 %*) were significantly (p<0.05) attenuated. mRNA for tumor necrosis factor‐α (TNF‐α), IL‐1β, monocyte chemoattractant protein‐1 (MCP‐1) and IL‐17RA in the PVN was measured by real‐time qPCR. Knockdown efficiency of IL‐17RA siRNA was confirmed by a reduction (−55%) of IL‐17RA mRNA level in the PVN. Additionally, the mRNA levels of TNF‐α (1.12 ± 0.24 vs. 0.51 ± 0.11*), IL‐1β (1.05 ± 0.16 vs. 0.64 ± 0.09*), and MCP‐1 (1.01 ± 0.10 vs. 0.60 ± 0.10*) induced by IV IL‐17A were significantly reduced in the PVN in rats pretreated with IL‐17RA siRNA. These data indicate that systemically administered IL‐17A acts upon IL‐17RA in the PVN to increase the expression of inflammatory mediators that drive sympathetic excitation, suggesting that PVN plays an important role in mediating the effects of circulating IL‐17A on sympathetic drive and cardiovascular function in inflammatory conditions such as hypertension and heart failure. IL‐17RA in the PVN is a potential target for therapeutic intervention in these diseases.Support or Funding InformationThis research was supported by NIH/NHLBI RO1 HL139521.