IL (Interleukin)-17A Acts in the Brain to Drive Neuroinflammation, Sympathetic Activation, and Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2021-11, Vol.78 (5), p.1450-1462
• Main Authors: Cao, Yiling, Yu, Yang, Xue, Baojian, Wang, Ye, Chen, Xiaolei, Beltz, Terry G., Johnson, Alan Kim, Wei, Shun-Guang
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier; Brain - physiology; Hypertension - etiology; Inflammation Mediators - physiology; Interleukin-17 - pharmacology; Male; Neuroinflammatory Diseases - chemically induced; Paraventricular Hypothalamic Nucleus - physiology; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-17 - physiology; Sympathetic Nervous System - physiology; Transcriptional Activation
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.121.18219

IL (Interleukin)-17A is a key inflammatory mediator contributing to chronic tissue inflammation. The present study sought to determine whether IL-17A plays a role in regulating neuroinflammation, hemodynamics, and sympathetic outflow in normal and hypertensive animals. In urethane-anesthetized rats, intravenous injection of IL-17A induced dramatic and prolonged increases in blood pressure, heart rate, and renal sympathetic nerve activity, which were significantly attenuated by an IL-17RA (IL-17 receptor A) siRNA in the hypothalamic paraventricular nucleus (PVN). Either intracerebroventricular or PVN microinjection of IL-17A also elicited a similar excitatory response in blood pressure, heart rate, and renal sympathetic nerve activity. Intravenous injection of IL-17A upregulated the mRNA level of IL-17A, IL-17F, and IL-17RA in the PVN. Additionally, intravenous injection of IL-17A activated brain-resident glial cells and elevated the gene expression of inflammatory cytokines and chemokines in the PVN, which were markedly diminished by PVN microinjection of IL-17RA siRNA. Pretreatments with microglia or astrocyte inhibitors attenuated the increase in blood pressure, heart rate, and renal sympathetic nerve activity in response to PVN IL-17A. Moreover, intracerebroventricular injection of IL-17A activated TGF (transforming growth factor)-β activated kinase 1, p44/42 mitogen-activated protein kinase, and transcriptional nuclear factor κB in the PVN. IL-17A interacted with tumor necrosis factor-α or IL-1β synergistically to exaggerate its influence on hemodynamic and sympathetic responses. Central intervention suppressing IL-17RA in the PVN significantly reduced angiotensin II–induced hypertension, neuroinflammation, and sympathetic tone in the rats. Collectively, these data indicated that IL-17A in the brain promotes neuroinflammation to advance sympathetic activation and hypertension, probably by a synergistic mechanism involving the interaction with various inflammatory mediators within the brain.