Cytokines Driving Sympathetic Nervous System Activation in the Subfornical Organ: Implications for Heart Failure and Hypertension


Subfornical Organ Heart Failure Hypertension
Subfornical Organ – Heart Failure – Hypertension

Update at BrainImmuneA recent study published in Hypertension demonstrates that cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α acting at the level of the subfornical organ induce the expression of inflammatory and excitatory mediators that subsequently drive sympathetic nervous system activation.

The subfornical organ (SFO), a highly vascularized structure is a circumventricular organ that lacks a blood–brain barrier. Previous research indicates this brain structure is a crucial ‘sensor’ for peripheral inflammation, mediating the central effects of certain pro-inflammatory cytokines, and thus, contributing to an increase in autonomic and neuro-hormonal output.

The SFO is rich in angiotensin-converting enzyme (ACE) and in angiotensin II (ANG II) type-1 receptors (AT1R), key components of the brain renin–angiotensin system (RAS) that activates subfornical organ neurons and drives sympathetic nerve activity in pathophysiological states like hypertension and HF. PICs contribute to upregulation of brain RAS activity in the hypothalamic paraventricular nucleus (PVN), another brain region that has been implicated in the sympathetic excitation and cardiovascular dysfunction, in hypertension and HF.

Cyclooxygenase (COX), the key enzyme regulating the production of prostaglandin E2 (PGE2), is also abundantly expressed in the highly vascularized SFO. PGE2 increases the firing rate of subfornical organ neurons by disinhibiting inhibitory γ-aminobutyric acid inputs. ANG II infusion induced hypertension is reportedly dependent on the activity of constitutively expressed COX-1 in the subfornical organ, and PIC-dependent induction of COX-2 in perivascular macrophages has been implicated in the pathophysiology of HF. Thus, inflammatory mechanisms that increase brain RAS activity or PGE2 production in SFO might be expected to increase sympathetic nerve activity.

In the Hypertension study Shun-Guang Wei and colleagues from the University of Iowa Carver College of Medicine, Iowa City, IA examined potential mechanisms in the subfornical organ, and downstream in the PVN, that might mediate cardiovascular and autonomic responses to circulating PICs.

The investigators report that (1) localized microinjections of TNF-α and IL-1β into the SFO increase BP, HR, and RSNA, closely mimicking the effects of systemically administered TNF-α and IL-1β; (2) pretreating the SFO with microinjections of agents that counter RAS and COX-2 activity attenuates the cardiovascular and sympathetic responses to SFO microinjections of PICs; (3) TNF-α and IL-1β receptor immunoreactivity is colocalized with AT1R-like, ACE, COX-2, and EP3 receptor immunoreactivity on subfornical organ neurons; and (4) subfornical organ microinjections of TNF-α and IL-1β upregulate mRNA for key components of the RAS (ACE and AT1R) and mediators of central inflammation (TNF-α and IL-1β, their receptors and COX-2) in both SFO and PVN.

These findings suggest that the SFO-mediated acute sympathoexcitatory response to PICs depends on the ambient level of RAS and COX-2 activity and that PICs act within the subfornical organ to increase RAS and COX-2 activity.

The authors provide evidence that IL-1β and TNF-α up-regulate mediators and mechanisms that increase the brain renin–angiotensin system (RAS) activity or prostaglandin E2 production in the SFO of male Sprague–Dawley rats.

This study provides new insights into the central mechanisms driving neurohumoral excitation in cardiovascular disorders like HF and hypertension.

The SFO is directly exposed to blood-borne signals and peripheral cytokines, and it projects straight to the cardiovascular autonomic nuclei.

The authors suggest that through the above mentioned effects and mechanisms, peripheral pro-inflammatory cytokines are able to drive a chronic and sustained hyperactivity of the sympathetic nervous system observed in pathologic states such as heart failure or some forms of hypertension.

In addition, according to the authors, these mechanisms and pathogenic loops can be amplified by other excitatory mediators, like angiotensin II and aldosterone that circulate in chronic states like heart failure and hypertension.

Source: Hypertension, 2015, 65:1126-33. doi: 10.1161/HYPERTENSIONAHA.114.05112. Epub 2015 Mar 16.
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A 2017 Editorial Focus article by Song Yao, Michael McKinley and Clive May discusses recently identified mechanisms and pathways that contribute to heart failure. It appears that a major mechanism along these lines includes the action of circulating proinflammatory cytokines, such as TNF-α and IL-1.

Thus, new research exploring the roles and actions of proinflammatory cytokines in the brains of animals with heart failure, demonstrated that peripheral administration of proinflammatory cytokines activates the sympathetic nervous system, presumably via a direct central action.

How this might be achieved?

Yao et al. summarize recent evidence indicating:

  • cytokines, such as TNF-α and IL-1β, may activate receptors on brain endothelial and perivascular cells and signal via cyclooxygenase (COX)-2 and PGE2.
  • an active transport of cytokines such as TNF-α and IL-1β across the blood-brain barrier.
  • a direct action of TNF-α on the sensory circumventricular organs of the brain (see Figure below).

proinflammatory cytokines subfornical organFigure: The damaged heart releases proinflammatory cytokines such as TNF-α, which can activate neurons in sensory circumventricular organs such as the subfornical organ (SFO). The SFO has projections to the hypothalamic paraventricular nucleus (PVN), which project directly, or indirectly via the rostral ventrolateral medulla (RVLM), to the preganglionic sympathetic neurons in the intermediolateral cell column (IML) in the spinal cord to increase sympathetic nerve activity. The increases in sympathetic nerve activity to the heart and kidney have detrimental actions that enhance the progression of the disease. COX-2, cyclooxygenase-2; RAS, renin-angiotensin system; TNFR1, TNF receptor 1. From: Circumventing a broken heart: cytokines and the subfornical organ by Song Yao, Michael McKinley and Clive May; Am J Physiol Heart Circ Physiol. 2017 Oct 1;313(4):H729-H731.

Of note, it is known that the sensory circumventricular organs (located along the wall of the third and fourth ventricle) are specialized brain nuclei that lack an intact blood-brain barrier due to the presence of fenestrated capillaries. There are three of these specialized structures in the brain: the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis in the anterior wall of the third ventricle and the area postrema located on the floor of the fourth ventricle.

The above-discussed mechanism by which TNF-α and TNFR1, acting in the SFO, drive increased sympathetic activity in rats with heart failure is further substantiated by recent published evidence with reducing TNFR1 expression in the SFO of heart failure rats. This was related to significantly lower plasma levels of norepinephrine compared with vehicle-injected rats.

The authors conclude that the sensory circumventricular organs in the brain are attractive sites for targeted therapies due to the absence of a blood-brain barrier. Thus, more research is needed to clarify the brain mechanisms leading to the central generation of increased sympathetic tone in heart failure.

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