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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: Hypertension. 2013 May 13;62(1):118–125. doi: 10.1161/HYPERTENSIONAHA.113.01404

Subfornical Organ Mediates Sympathetic and Hemodynamic Responses to Blood-borne Pro-Inflammatory Cytokines

Shun-Guang Wei 1, Zhi-Hua Zhang 1, Terry G Beltz 2, Yang Yu 1, Alan Kim Johnson 2, Robert B Felder 1,3
PMCID: PMC3769944  NIHMSID: NIHMS481592  PMID: 23670302

Abstract

Pro-inflammatory cytokines play an important role in regulating autonomic and cardiovascular function in hypertension and heart failure. Peripherally administered pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) act upon the brain to increase blood pressure (BP), heart rate (HR) and sympathetic nerve activity. These molecules are too large to penetrate blood brain barrier (BBB), and so the mechanisms by which they elicit these responses remain unknown. We tested the hypothesis that the subfornical organ (SFO), a forebrain circumventricular organ that lacks a BBB, plays a major role in mediating the sympathetic and hemodynamic responses to circulating pro-inflammatory cytokines. Intracarotid artery (ICA) injection of TNF-α (200 ng) or IL-1β (200 ng) dramatically increased mean BP (MBP), HR and renal sympathetic nerve activity (RSNA) in rats with sham lesions of the SFO (SFO-s). These excitatory responses to ICA TNF-α and IL-1β were significantly attenuated in SFO-lesioned (SFO-x) rats. Similarly, the increases in MBP, HR and RSNA in response to intravenous (IV) injections of TNF-α (500 ng) or IL-1β (500 ng) in SFO-s rats were significantly reduced in the SFO-x rats. Immunofluorescent staining revealed a dense distribution of the p55 TNF-α receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, in the SFO. These data suggest that SFO is a predominant site in the brain at which circulating pro-inflammatory cytokines act to elicit cardiovascular and sympathetic responses.

Keywords: subfornical organ, pro-inflammatory cytokines, sympathetic drive, cytokine receptors

Introduction

Inflammation has been implicated in the development of a variety of cardiac, cerebrovascular and metabolic diseases, such as heart failure, hypertension, atherosclerosis, stroke, obesity and diabetes mellitus.1-5 Levels of inflammatory mediators are augmented in the circulation and tissues in these pathophysiological conditions. Growing evidence indicates that systemic inflammation contributes to the progression of these diseases by activating the sympathetic nervous system,6, 7 but the mechanisms remain unclear.

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are two representative members of the pro-inflammatory cytokine family that act upon the brain to increase blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA).8, 9 How these molecules that are lipophobic and too large to penetrate the blood brain barrier (BBB) activate the sympathetic nervous system remains a mystery. TNF-α and IL-1β receptors are widely distributed in the cerebral microvasculature and other elements of the BBB, including the choroid plexus and circumventricular organs (CVOs) that lack a BBB.10, 11 There is strong support for the hypothesis that circulating cytokines activate their receptors on endothelial and perivascular cells of the brain microvasculature to induce cyclooxygenase-2 (COX-2) activity and the production of prostaglandin E2 (PGE2), which crosses the BBB and can elicit sympathetic responses.12 In vitro brain slice work has demonstrated that IL-1β activates neurons in the subfornical organ (SFO)29, a forebrain CVO. The possibility that circulating pro-inflammatory cytokines might increase sympathetic drive by activating their receptors on cellular elements of CVOs has not previously been explored.

The present study examined the potential role of the SFO as a link between blood-borne pro-inflammatory cytokines and central mechanisms driving sympathetic excitation. The SFO has direct and indirect connections to the hypothalamic paraventricular nucleus (PVN),13, 14 a key cardiovascular and autonomic brain region that contains pre-sympathetic and neuroendocrine neurons. We chose to study the SFO because of its recognized role in the pathogenesis of heart failure,15 hypertension16, 17 and the febrile response.18

Methods

Animals

Experiments were performed on adult male Sprague-Dawley rats (300-350g), purchased from Harlan Sprague Dawley (Indianapolis, IN). Animals were housed in Animal Care Facility at the University of Iowa and fed rat chow ad libitum. All experimental procedures were approved by the University of Iowa Institutional Animal Care and Use Committee. The experimental protocols were conducted in accordance with the National Institutes of Health “Guide for the Care and Use of Laboratory Animals.”

Drug Administration

Intracarotid artery (ICA) injections of TNF-α and IL-1β were made via a rostrally directed PE-20 cannula inserted into the left common carotid artery, with the tip placed in the bifurcation. ICA injections are thought to target primarily the forebrain in rats.19 Intravenous (IV) injections of TNF-α and IL-1β were performed via a PE-50 cannula placed in the left femoral vein. The IV injections allowed TNF-α and IL-1β to access receptors in the periphery and all regions of the brain. TNF-α and IL-1β were purchased from Fitzgerald (Acton, MA) and Millipore (Billerica, MA), respectively, and dissolved in 0.9% saline. Both drugs were administered as a bolus injection (200 ng in 4 μl ICA; 500 ng in 10 μl IV) followed by a 15-μl saline flush. Doses were based on a previous publication.8

Experimental protocols

Hemodynamic and sympathetic effects of TNF-α and IL-1β

Rats that had undergone SFO lesions (SFO-x, n=22) or a sham procedure (SFO-s, n=22) 1-3 week earlier were anesthetized and prepared for sympathetic and hemodynamic recordings to determine the effects of an ICA or IV injection of TNF-α and IL-1β on mean BP (MBP), HR and RSNA. Each rat underwent only one cytokine injection. 0.9% Saline served as vehicle (VEH).

TNF-α and IL-1β receptors in SFO and PVN

Rats (n=6) were euthanized and transcardially perfused with heparinized saline followed by 4% paraformaldehyde in 0.1M PBS. The collected brains were cut into 16-micron coronal sections for immunofluorescent staining of SFO and PVN.

There are two types of TNF-α receptors, a 55 KD transmembrane protein (TNFR1) and a 75 KD transmembrane protein (TNFR2). The TNFR1 is more widely expressed in the brain, particularly in barrier regions including the CVOs.11 We used anti-TNFR1 antibody (Catalog # ab19139, Abcam, Cambridge, MA) to identify TNFR1. IL-1 receptor accessory protein (IL-1RAcP) is a subunit of the IL-1 receptor that is also predominantly located in barrier regions and CVOs20 and mediates the effects of IL-1β. We used an antibody (Catalog # I8153, Sigma-Aldrich, St. Louis, MO) to IL-1RAcP to identify the IL-1 receptor. Antibodies to cell specific markers were used to determine the co-localized expression of TNFR1 and IL-1RAcP with neurons (NeuN, MAB377, Millipore) and astrocytes (GFAP, #3670, Cell Signaling).

Specific Materials and Methods

Please see the online data supplement (http://hyper.ahajournals.org).

Results

Hemodynamic and sympathetic effects of blood-borne cytokines in SFO-s and SFO-x rats

ICA Administration

ICA injections of TNF-α (n=6, Figure 1A, C) and IL-1β (n=6, Figure 2A, C) induced similar substantial and long-lasting increases in BP, HR and RSNA in SFO-s rats. Both began within 10-20 minutes of the ICA injection. The peak increases in MBP (TNF-α: 21.8 ± 4.1 mmHg; IL-1β: 22.9 ± 3.1 mmHg) occurred at 1 hour and was sustained at a higher than baseline level for the remainder of the 4-5 hour recording period. The peak increase in HR (TNF-α: 101.8 ± 11.3 bpm; IL-1β: 82.4 ± 8.4 bpm ) and RSNA (TNF-α: 114.5 ± 12.2 % change; IL-1β: 99.3 ± 12.8 % change) occurred 2-3 hours after the ICA injections and lasted for 4-5 hours and even longer in most cases.

Figure 1.

Figure 1

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Representative tracings (A, B) and grouped data (C) showing effects of intracarotid artery (ICA) injection of TNF-α (200 ng) on blood pressure (BP, mmHg), heart rate (HR, bpm) and renal sympathetic nerve activity (RSNA), windowed (spikes/s) and integrated (mV), in sham subfornical organ-lesioned (SFO-s) and SFO-lesioned (SFO-x) rats. Arrows indicate the initiation of the injections. MBP, mean blood pressure; ΔRSNA (%), percent change from baseline in integrated RSNA. All values are expressed as the means ± SE. * p<0.05 compared to baseline in either SFO-s or SFO-x. † p<0.05 compared to SFO-s. Scale Bar: 20 min.

Figure 2.

Figure 2

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Representative tracings (A, B) and grouped data (C) showing effects of intracarotid artery (ICA) injection of IL-β (200 ng) on blood pressure (BP, mmHg), heart rate (HR, bpm) and renal sympathetic nerve activity (RSNA), windowed (spikes/s) and integrated (mV), in sham subfornical organ-lesioned (SFO-s) and SFO-lesioned (SFO-x) rats. Arrows indicate the initiation of the injections. MBP, mean blood pressure; ΔRSNA (%), percent change from baseline in integrated RSNA. All values are expressed as the means ± SE. * p<0.05 compared to baseline in either SFO-s or SFO-x. † p<0.05 compared to SFO-s. Scale Bar: 20 min.

In the SFO-x rats, ICA injections of TNF-α (n=6, Figure 1B, C) and IL-1β (n=6, Figure 2B, C) induced smaller, delayed responses in BP, HR and RSNA. There were no significant changes in MBP, HR or RSNA within the first two hours after the injections, and the peak responses of BP (TNF-α: 6.9 ± 2.3 mmHg; IL-1β: 8.5 ± 2.0 mmHg), HR (TNF-α: 46.8 ± 8.9 bpm; IL-1β: 41.5 ± 7.6 bpm) and RSNA (TNF-α: 50.4 ± 10.5% changes; IL-1β: 41.3± 7.3% changes) occurred 3-4 hours after the injections.

ICA injections of an equal volume of vehicle (0.9% saline) had no effects on MBP, HR and RSNA in SFO-s (n=4) or SFO-x (n=4) rats (Figure S1). The baseline levels of MBP (100.4 ± 3.2 mmHg), HR (326 ± 8 bpm) and integrated RSNA (10.8 ± 3.7 mV) in SFO-s rats did not differ significantly from the baseline levels of MBP (98.6 ±3.1 mmHg), HR (328 ± 9 bpm) and integrated RSNA (10.4 ± 3.4 mV) in SFO-x rats.

IV Administration

Similar to ICA injections, IV injection of either TNF-α (n=5, Figure 3A, C) or IL-1β (n=5, Figure 4A, C) markedly augmented BP, HR and RSNA in SFO-s rats. The responses to TNF-α and IL-1β began within 10-20 minutes of the IV injection. The peak increases in MBP (TNF-α: 18.4 ± 2.4 mmHg; IL-1β: 18.0 ± 3.2 mmHg) occurred at 1 hour, and MBP was sustained at a higher than baseline level for the remainder of the 4-5 hour recording period. The peak HR (TNF-α: 80.6 ± 10.0 bpm; IL-1β: 71.3 ± 8.3 bpm) and RSNA (TNF-α: 89.2 ± 9.3% change; IL-1β: 85.1 ± 10.8% change) responses occurred 2-3 hours after the injection and lasted for 4-5 hours and even longer in most cases.

Figure 3.

Figure 3

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Representative tracings (A, B) and grouped data (C) showing effects of intravenous (IV) injection of TNF-α (500 ng) on blood pressure (BP, mmHg), heart rate (HR, bpm) and renal sympathetic nerve activity (RSNA), windowed (spikes/s) and integrated (mV), in sham subfornical organ-lesioned (SFO-s) and SFO-lesioned (SFO-x) rats. Arrows indicate the initiation of the injections. MBP, mean blood pressure; ΔRSNA (%), percent change from baseline in integrated RSNA. All values are expressed as the means ± SE. * p<0.05 compared to baseline in either SFO-s or SFO-x. † p<0.05 compared to SFO-s. Scale Bar: 20 min.

Figure 4.

Figure 4

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Representative tracings (A, B) and grouped data (C) showing effects of intravenous (IV) injection of IL-1β (500 ng) on blood pressure (BP, mmHg), heart rate (HR, bpm) and renal sympathetic nerve activity (RSNA), windowed (spikes/s) and integrated (mV), in sham subfornical organ-lesioned (SFO-s) and SFO-lesioned (SFO-x) rats. Arrows indicates the initiation of the injection. MBP, mean blood pressure; ΔRSNA (%), percent change from baseline in integrated RSNA. All values are expressed as the means ± SE. * p<0.05 compared to baseline in either SFO-s or SFO-x. † p<0.05 compared to SFO-s. Scale Bar: 20 min.

In the SFO-x rats, the increases in MBP, HR and RSNA to IV TNF-α (n=5, Figure 3B, C) or IL-1β (n=5, Figure 4B, C) were substantially blunted. However, the early responses (first 2 hours) were attenuated rather than completely blocked, as the responses to the ICA injection had been. The peak MBP (TNF-α: 8.3 ± 2.1 mmHg; IL-1β: 7.1 ± 2.4 mmHg) responses occurred at 1-1.5 hours after the IV injection. The peak HR (TNF-α: 40.0 ± 7.7 bpm; IL-1β: 37.3 ± 7.9 bpm) and RSNA (TNF-α: 45.8 ± 9.6% change; IL-1β: 45.1 ± 7.8% change) responses occurred 2-3 hours after the IV injection.

The baseline levels of MBP, HR and RSNA were similar to those in the ICA study group. IV injections of an equal volume of vehicle (0.9% saline, n=4) had no effects on MBP, HR and RSNA in SFO-s or SFO-x rats (data not shown).

Histological assessment of the SFO lesions

Twenty-two of 28 animals in which SFO lesions were made had at least 80% ablation of the SFO and constituted the SFO-x group. Representative images of the SFO region from SFO-s and SFO-x rats are shown in Figure S2. The excitatory responses induced by ICA and IV TNF-α or IL-1β remained intact in the 6 animals with incomplete SFO lesions. (Figure S3)

Cytokine receptors in the SFO and PVN of normal rats

Immunofluorescent studies revealed intense evenly distributed expression of TNFR1 immunoreactivity in the SFO (Figure 5A, n=6) of normal rats. Confocal immunofluorescent images indicated that TNFR1 was expressed by neurons, astrocytes and unlabeled cellular elements in the SFO (Figure 5A). There was no significant expression of TNFR1 in the PVN in these normal rats (Figure S4).

Figure 5.

Figure 5

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Laser confocal images show expression of TNF-α receptor 1 (TNFR1, A) and IL-1 receptor accessory protein (IL-1RAcP, B) in neurons (upper panels) and astrocytes (lower panels) in SFO. The 3 right panels in both A and B are higher-power views taken from the regions indicated by the red rectangles in the left panels. Upper panels of A and B: Green, TNFR1 or IL-1RAcP; Red: neuronal marker NeuN; Yellow: Merged. Lower panels of the A and B: Green, TNFR1 or IL-1RAcP; Red: astrocyte marker GFAP; Yellow: Merged.

IL-1RAcP was also intensely expressed in the SFO (Figure 5B, n=6). Like TNFR1, IL-1RAcP was evenly expressed throughout the SFO by neurons, astrocytes, and unlabeled cellular elements (Figure 5B). Expression of IL-1RAcP in the PVN was sparse in the normal rats, and found only in the magnocellular subdivision of the PVN (Figure S4).

Discussion

The present study suggests an important role for the SFO in mediating the sympathetic and hemodynamic responses to circulating pro-inflammatory cytokines. The major findings are: 1) peripheral injections of TNF-α and IL-1β induce pronounced increases in MBP, HR and RSNA that are largely dependent on an intact SFO; and 2) receptors for TNF-α and IL-1β are abundantly expressed by neurons, astrocytes and other cellular elements of the SFO. These findings in normal rats suggest that the SFO may be a primary interface between peripheral inflammation and central nervous system mechanisms driving sympathetic activity in chronic inflammatory conditions like hypertension and heart failure.

We utilized two strategies to determine the role of the SFO in cytokine-induced sympathetic excitation. ICA injections of TNF-α and IL-1β, which preferentially target the forebrain region,19 allowed an assessment of central nervous system (CNS)-mediated effects while minimizing any potential influences of peripheral cytokine receptors. The ICA dose, given intravenously, had very little effect. In this protocol, the SFO lesion prevented cytokine-induced cardiovascular and sympathetic responses in the first 100 minutes, though a small increase in all variables was observed thereafter. These results confirmed an important role for the SFO in mediating the effects of cytokines reaching the forebrain. We used IV injections of TNF-α and IL-1β to assess the role of the SFO in the response to cytokines in the systemic circulation, where they also have access to peripheral cytokine receptors (e.g., in tissues innervated by vagal afferents) and cytokine receptors in other brain regions in which they are known to exert their central effects. In this protocol, that more closely resembles pathophysiological conditions, the SFO lesion also substantially reduced the cardiovascular and sympathetic responses.

Several mechanisms have been invoked to explain the central influences of circulating cytokines (Figure 6). These include induction of COX-2/PGE2 in cells of the BBB,10, 12 activation of cells in the CVOs that are exposed to circulating cytokines,11 active transport of cytokines across the BBB21 and activation of vagal afferent fibers.22, 23 We have previously demonstrated that cytokine induction of COX-2 in perivascular cells plays a role in the sympathetic excitation in heart failure.12 Others have shown that cytokine induction of COX2/PGE2 activates the hypothalamic-pituitary-adrenal axis, a response that apparent arises from the brain stem and is not affected by interrupting the descending projections to PVN from the forebrain CVOs.24 In contrast, SFO lesions can prevent the cytokine-induced febrile response.18 The present study suggests that the SFO may be the predominant site in the brain at which circulating pro-inflammatory cytokines act to elicit excitatory cardiovascular and sympathetic responses. One or more of the other putative mechanisms indicated in Figure 6 may also contribute to the responses to circulating cytokines.

Figure 6.

Figure 6

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The schematic illustrates putative pathways by which circulating pro-inflammatory cytokines (TNF-α and IL-1β) may influence sympathetic activity. All except the vagal afferent pathway are potentially excitatory. CVOs: Circumventricular organs, PVN: paraventricular nucleus of hypothalamus, SFO: Subfornical organ, RVLM: Rostral ventrolateral medulla, CVLM: Caudal ventrolateral medulla, OVLT: Organum vasculosum of the lamina terminalis, NTS: Nucleus tractus solitarius, BBB: blood brain barrier, COX-2: cyclooxygenase-2, PGE2: prostaglandin E2.

An obvious question that arises is: How do cytokines act upon the SFO to elicit a sympatho-excitatory response? SFO-dependent cytokine-induced sympathetic and hemodynamic responses are characterized by a delayed onset (10-20 minutes after ICA or IV injection) and a prolonged duration (>4 hours). These features suggest the induction of cellular mechanisms leading to increased neuronal excitability, rather than direct synaptic activation. The SFO is a particularly rich environment for cytokine-induced molecular signaling, with TNF-α and IL-1β receptors expressed on multiple cell types in a nucleus exposed to the circulation. Astrocytes, microglia, perivascular macrophages and endothelial cells all express cytokine receptors. Astrocytes produce chemokines,25 and angiotensinogen,26 the precursor of angiotensin II (ANG II); microglia produce a variety of inflammatory mediators including pro-inflammatory cytokines, chemokines, COX-2/PGE2 and reactive oxygen species;27, 28 endothelial and perivascular cells produce COX-2 and PGE22. All of these non-neuronal mechanisms may contribute to the overall excitability of SFO neurons without directly activating them. How, exactly, cytokine receptors on the SFO neurons themselves contribute remains uncertain – in an in vitro brain slice preparation, SFO neurons responded to IL-1β within seconds to minutes, but the mechanism was not determined.29

The concept of the SFO as a sensor of peripheral inflammation and orchestrator of the central cardiovascular and sympathetic response is consistent with its known functions. The SFO has long been known as the primary CNS sensor of circulating ANG II, communicating its message to brain centers30 that regulate blood pressure, sympathetic outflow, drinking behavior and neuroendocrine release of vasopressin, oxytocin and adrenocorticotropic hormone.31-33 Destruction of the SFO attenuates the development of hypertension in several humorally-driven experimental models,16, 17, 34 and the progression of heart failure after myocardial infarction.15,35 More recently, oxidative stress in the SFO induced by a slow-pressor dose of ANG II has been shown to drive immune-mediated cardiovascular dysfunction in hypertension.36 It is of note in this regard that pro-inflammatory cytokines also induce oxidative stress in brain tissue, independently 37 and perhaps by upregulating the activity of the brain renin-angiotensin system (RAS).38 The present results raise the possibility of a positive feedback loop in conditions like hypertension and heart failure whereby circulating products of peripheral immune activation promote oxidative stress in SFO, amplifying the peripheral immune response and perhaps the effects of circulating ANG II. The interaction of pro-inflammatory cytokines with the systemic and brain RAS at the SFO level is an important area for future research in hypertension and heart failure.

Previous studies have emphasized the sympatho-excitatory role of pro-inflammatory cytokines in the PVN in heart failure39 and hypertension.40 It may be presumed that cardiovascular and sympathetic responses to cytokine activation of the SFO depend upon activation of pre-sympathetic and perhaps neuroendocrine neurons downstream in the PVN. Notably, in normal rats in the present study, TNFR1 were sparse in the PVN compared with their dense representation in the SFO. Similarly, IL-1 receptors were expressed only sparsely and mostly in the magnocellular subdivision of PVN that is associated with vasopressin release. These results are consistent with previous immunohistochemical studies in normal rats 11, 41 and with in vitro data from normal rats suggesting that IL-1β excites PVN neurons indirectly via disinhibition of surrounding inhibitory GABAergic neurons.42

These conditions are altered in heart failure and hypertension. TNF-α and IL-1β are upregulated in the PVN39, 40 by mechanisms that are not yet fully understood, and pro-inflammatory cytokines are known to upregulate their own receptors.43 We know that IL-6 receptors are upregulated in the PVN in heart failure rats,44 and preliminary data (unpublished) from our laboratory suggests that message for TNF-α and IL-1β receptors is also increased in the PVN in heart failure. Whether the actions of circulating cytokines in the SFO facilitate the expression of TNF-α and IL-1β and their receptors downstream in the PVN, or whether other mechanisms are involved, remains to be determined.

Limitations of the study

We can't exclude the possibility that an increase in circulating ANG II, precipitated by peripheral cytokine effects or cytokine-induced increases in renal sympathetic nerve activity, may have contributed to these responses; plasma ANG II levels were not measured. The fact that the lower ICA doses of TNF-α and IL-1β elicited at least as prominent a response as the higher IV doses, but only a minimal response when administered peripherally, argues against direct cytokine stimulation of RAS activity in peripheral tissues as a factor contributing to the initial rise in pressure. However, the cytokine-induced increase in renal sympathetic nerve activity, by increasing renal renin release, may have resulted in increased levels of circulating ANG II that may have contributed to the late sustained responses. In addition, we can't exclude the possibility that leakage of the peripherally injected TNF-α and IL-1β through the injured BBB allowed access to other central nuclei that may have contributed to the residual responses we observed in the SFO-lesioned rats. We did not investigate the expression of cytokine receptors in other hypothalamic nuclei. Finally, while the SFO lesion substantially reduced the cardiovascular and sympathetic responses to acutely administered TNF-α and IL-1β, we cannot exclude a role for other CVOs and other mechanisms (induction of COX-2/PGE2 in the microvasculature; passage of cytokines across the BBB) in the residual responses. And importantly, in chronic inflammatory disease states with persistently elevated plasma cytokine levels, other central and peripheral mechanisms may assume a more prominent role.

Perspectives

This study identifies the SFO as an essential central nervous system site at which systemically administered pro-inflammatory cytokines act to influence cardiovascular function and sympathetic activity in normal rats. We propose that the SFO may serve a similar function in heart failure, in which circulating cytokines are chronically elevated. The SFO is a likely site for central interactions between circulating cytokines and angiotensin II - as well as locally produced brain cytokines and the brain RAS - that may determine the activity of presympathetic and neuroendocrine neurons downstream in the PVN. Other mechanisms by which cytokines might act within the SFO to increase sympathetic discharge are induction of COX-2 and synthesis of PGE245 by endothelial cells, microglia or perivascular macrophages, and induction of inflammatory chemokines25 whose receptors are abundant in the SFO and which have recently been shown to contribute to sympathetic drive in heart failure.46 Further investigations are needed to determine the molecular and cellular mechanisms underlying the effects of blood-borne cytokines on the SFO and downstream autonomic nuclei, and the role of the SFO in inflammatory cardiovascular disease states.

Supplementary Material

1

Novelty and Significance.

1) What Is New?

  • Intracarotid artery and intravenous injections of TNF-α or IL-1β induce pronounced increases in BP, HR and RSNA that are largely dependent on an intact subfornical organ.

  • Receptors for TNF-α and IL-1β are abundantly expressed in neurons and astrocytes in the subfornical organ.

2) What Is Relevant?

  • Systemic inflammation contributes to activation of the sympathetic nervous system in hypertension and heart failure.

  • This study demonstrates a major role for the subfornical organ as an interface between systemic inflammation and sympathetic activation.

3) Summary

  • The data suggest that the subfornical organ senses circulating cytokines and regulates sympathetic and hemodynamic responses to peripheral inflammation in cardiovascular disease states.

Acknowledgments

None

Sources of Funding: This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development and by National Heart, Lung and Blood Institute and the National Institute of Mental Health of the National Institutes of Health under award numbers R01HL073986 (to R.B.F.), RO1HL096671 (to R.B.F.), PO1HL014388 (to A.K.J.), RO1HL098207 (to A.K.J.) and RO1MH080241 (to A.K.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Disclosures: None

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