Blood-borne interleukin-1β acts on the subfornical organ to upregulate the sympathoexcitatory milieu of the hypothalamic paraventricular nucleus

Abstract

We previously reported that microinjection of the proinflammatory cytokine interleukin-1β (IL-1β) into the subfornical organ (SFO) elicits a pressor response accompanied by increases in inflammation and renin-angiotensin system (RAS) activity in the SFO and hypothalamic paraventricular nucleus (PVN). The present study sought to determine whether blood-borne IL-1β induces similar neurochemical changes in the SFO and PVN and, if so, whether increased inflammation and RAS activity at the SFO level orchestrate the sympathoexcitatory response to circulating IL-1β. In urethane-anesthetized male Sprague-Dawley rats, intravenous injection of IL-1β (500 ng) increased blood pressure, heart rate, renal sympathetic nerve activity, and mRNA for angiotensin-converting enzyme, angiotensin II type 1a receptor, cyclooxygenase-2, tumor necrosis factor-α, and IL-1β, as well as the tumor necrosis factor-α p55 receptor and the IL-1 receptor, in the SFO and PVN. Pretreatment with SFO microinjections of the angiotensin II type 1a receptor blocker losartan (1 µg), the angiotensin-converting enzyme inhibitor captopril (1 µg), or the cyclooxygenase-2 inhibitor NS-398 (2 µg) attenuated expression of these excitatory mediators in the SFO and downstream in the PVN and the IL-1β-induced pressor responses. An SFO lesion minimized the IL-1β-induced expression of inflammatory and RAS components as well as c-Fos, an indicator of neuronal excitation, in the PVN. These studies demonstrate that circulating IL-1β, which increases in cardiovascular disorders such as hypertension and heart failure, acts on the SFO to increase inflammation and RAS activity in the SFO and PVN and that intervening in these neurochemical processes in the SFO can significantly reduce the sympathetic response.

Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension

“…Conversely, both systemic PICs and brain PICs reciprocally interact with the RAS ( Winklewski et al, 2015 ). As previously noted, the body-brain communication of these two systems includes both afferent neural and the humoral pathways over which circulating ANG II and PICs activate the central neural network controlling cardiovascular function ( Wei et al, 2013 , 2015 , 2018 ). Because either the RAS or inflammatory mediators can contribute individually to the pathogenesis of hypertension, the interaction between RAS components and PICs are likely to have important synergistic effects ( Yu et al, 2013 ; Xue et al, 2016a ).…”

“…Recent studies demonstrate that the high BP of the spontaneously hypertensive rat (SHR) and ANG II-induced hypertension are accompanied by microglial activation within the PVN along with elevated PICs ( Shi et al, 2010 ; Shen et al, 2015 ). The increased levels of blood-borne and central PICs in cardiovascular disease states lead to the neurohumoral activation including sympathoexcitation and upregulation of central RAS activity ( Wei et al, 2015 , 2018 ). Blockade of brain microglia or targeted depletion of activated microglia within the PVN attenuates ANG II-induced hypertension, decreases PVN cytokines and reduces cardiac hypertrophy ( Shi et al, 2010 ; Shen et al, 2015 ).…”

Neuroinflammation in heart failure: new insights for an old disease

“…Indeed, it has recently been shown that blood‐borne IL‐1β upregulates pro‐inflammatory cytokines and RAS in the SFO and the PVN in healthy rats after 2–3 h, and that these changes are attenuated by microinjections of losartan directly into the SFO or after SFO destruction (Wei et al . ), demonstrating the strong relationship between RAS and neuroinflammation.…”

“…Plasma cytokines such as tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β can directly induce sympathoexcitation by exciting circumventricular organs (CVOs), like the subfornical organ (SFO) (Wei et al . , ; Simpson & Ferguson, ); or affect autonomic regulation indirectly by driving RAS activation via NF‐κB in deeper SNS control areas (Paul et al . ; Sciarretta et al .…”

Contribution of Oxidative Stress and Inflammation to the Neurogenic Hypertension Induced by Intermittent Hypoxia

“…They found that the increased BP and RSO induced by injections of TNF-α or IL-1β into the rat SFO were attenuated by microinjections of losartan and captopril in the SFO ( Wei et al, 2015 ). More recently, Wei et al (2018) found that the intravenous injection of IL-1β increased mRNA levels of the angiotensin-converting enzyme, AT1R, TNF-α, and IL-1β in the SFO and the PVN. Pretreatment with microinjections of losartan and captopril in the SFO attenuated the expression of these excitatory mediators in the SFO and in the PVN.…”