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promotes sleep
and is recovered in cervical lymph
1 Centre for Sleep and Chronobiology and 2 Departments of Immunology and Pathology, University of Toronto, Toronto, Ontario, Canada M5T 2S8
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Recent studies have shown that the
central nervous system (CNS) communicates with the periphery by the
drainage of cerebrospinal fluid and brain interstitial fluid into blood
and lymph. We hypothesized that tumor necrosis factor (TNF)-
would
not only influence the CNS by promoting sleep but also would be
directly transmitted into the peripheral immune system. Five hundred
nanograms of 125I-labeled TNF-
were injected into the lateral ventricles of the brain of six sheep and
sampled in venous blood and cervical and prescapular lymph every 30 min
for 6 h. 125I-TNF- was measured in lymph nodes
and control fat, skin, and muscle tissues 6 h postinjection.
125I-TNF- was detected in the cervical lymphatics within
the first 30 min and peaked within 2-3 h. 125I-TNF-
counts were elevated in the nodes of the head and neck region.
Polysomnographic recordings of four animals showed that TNF- induced
a significant increase in slow-wave sleep at postinjection hours
4 and
5. CNS TNF- and its direct drainage
into the lymphatic system may influence both the sleeping/waking brain
and peripheral immune functions.
lymph nodes; lymphatic drainage; cytokine; sheep; slow-wave sleep; tumor necrosis factor-
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE CENTRAL NERVOUS SYSTEM (CNS) and the immune system communicate through neural and endocrine pathways. These interactions occur through direct sympathetic innervation of immune organs (11); through the release of mediators from nerves situated near immune cells (23); by neuroendocrine signals, primarily the hypothalamic-pituitary axis (1); or by the drainage of cerebrospinal fluid (CSF) from the ventricles and subarachnoid space into the dural sinus blood via the arachnoid villi.
Fluid from the brain also drains into the head and neck lymphatics. CSF and brain interstitial fluid drain along the prolongations of the subarachnoid space around certain cranial nerves, including the olfactory, optic, trigeminal, and auditory nerves (7). The perineural extensions of the subarachnoid space may open directly into various tissues from which the prenodal lymphatics drain to lymph ducts. The drainage of CSF through lymphatic pathways has been well characterized in sheep. Radiolabeled albumin injected into the lateral ventricles of the brain drains into the lymph nodes in the head and neck region (3). As much as 40-48% of protein tracer introduced into the CSF is cleared into the lymphatic system (2), thus revealing the importance of this pathway for CSF drainage.
The evidence indicates that this pathway can transport molecules
originating in the brain to the lymphatic system. Given the role of the
lymph nodes in the immune response, immune factors produced in the
brain could potentially drain into the lymph nodes and influence the
immune response. Tumor necrosis factor (TNF)-, a cytokine produced
in the CNS by astrocytes (21) and microglial macrophages (13), may
influence the peripheral immune system through the lymphatic pathway.
TNF- is a potent immunomodulator in mediating lymphocyte
redistribution and extravascular lymphocyte infiltration (16, 17). In
addition, TNF- is involved in promoting sleep and fever (18). The
purpose of this study was to investigate and further characterize the
lymphatic pathway as a pathway of communication from the CNS to the
immune system and to determine whether an intracerebroventricular
injection of TNF- would promote sleep and be recovered in the
lymphatic system.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Tracers
and
solutions. Human TNF- was obtained
from R&D Systems (Minneapolis, MN) and
125I-human TNF- (500-1,000
Ci/mmol) from Amersham (Oakville, ON). 131I-labeled human serum albumin
(37 MBq/ml) was obtained from Merck Frosst (Kirkland, PQ). Artificial
CSF (aCSF) was prepared as described by Chodobski et al. (6).
Surgery. Surgery was performed on 10 female sheep 6-8 mo old weighing 30-45 kg. Each sheep was initially anesthetized with pentobarbital sodium and maintained under a general halothane anesthetic. In four sheep, lateral ventricle catheters and sleep-recording electrodes (Plastics One, Renoke, VA) were implanted during a single surgery. Six sheep underwent two surgeries. In the first surgery, catheters were implanted into the lateral ventricle of the brain. In the second surgery, lymphatic vessels and a jugular vein were cannulated after a 1-wk recovery from the first surgery.
As described by Boulton et al. (3), a sagittal incision was made in the sheep's scalp to reveal the posterior fontanelle and coronal sutures. Bilateral burr holes were made 1.5 cm anterior and 1.5 cm lateral to the posterior fontanelle. A single catheter guide screw was inserted into each hole, and a 16-gauge Novalon intravenous catheter (Becton Dickinson) was fed through the guide tube. To determine the correct placement of the catheter in the ventricle, a column of aCSF was attached to the catheter. Correct placement of the catheter was confirmed by a sudden drop of aCSF volume into the column.
Electrocorticogram (ECoG) electrodes were screwed into the skull ~8 mm each side of the midline and over the parietal and occipital regions of the cerebral cortex so that the electrode screw tips touched the dura matter. Electrooculogram (EOG) electrodes were screwed into the temporal bone. Electromyograms (EMG) wire electrodes were sutured into the superficial dorsal muscles of the neck. The electrodes were connected to a multiconnector socket that was fixed to the skull with acrylic cement.
Chronic indwelling catheters were implanted into the efferent cervical lymphatics and a jugular vein. A longitudinal incision was made along the sheep's neck, and lymphatics were exposed by dissecting the surrounding tissue. Once the lymphatics were exposed, an incision was made in the lymphatic vessel and a vinyl catheter (Dural Plastics and Engineering, Auburn, Australia) was inserted into the lumen and firmly tied with silk suture (20). Cervical lymphatics that were too small to cannulate were ligated to prevent possible delivery of radiolabeled tracer to the blood. All radiolabel tracer studies were performed 24 h after the sheep had recovered from the lymphatic surgical procedure.
Protocol 1. Sheep were maintained on a
12:12-h light-dark cycle (0700-1900 light). After the surgery,
sheep were housed in metabolic cages. One week after the surgery, 500 ng of TNF- were diluted in 1 ml of aCSF, and 500 µl were injected
into each lateral ventricle at 0900. For control experiments, equal
amounts of aCSF were used as injectant. Each sheep served as its own
control. On the day of the experiment, a flexible tether was connected to the multiconnector on the surface of the sheep's head, allowing freedom of movement to the sheep. The tether was connected to an
electronic swivel (Plastics One), which was connected to a Grass 7D
Polygraph in an adjacent room that recorded ECoG, EOG, and EMG activity.
The polygraph record was scored manually into periods of wake, drowsy, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. A closed-circuit TV camera was also used to visually monitor the behavior of the sheep from a remote site. The recordings were divided into 50-s epochs; each epoch was classified as either wake, drowsy, SWS, or REM sleep as follows. Wake was characterized by desynchronized low-voltage, fast-activity ECoG and positive tone in neck muscles; drowsy was characterized by a combination of desynchronized low-voltage and synchronized high-voltage activity in ECoG; SWS was characterized by synchronized high-voltage slow activity in ECoG with low tone in EMG; and REM sleep was characterized by desynchronized low-voltage, fast-activity ECoG, rapid eye movements (EOG), and no tone in EMG but some phasic activity in facial muscles [criteria of Ruckebusch (25)]. Body position was also monitored over the 6-h recording period.
Protocol 2. Ten microcuries
125I-TNF- (~500 ng) and 10 µCi 131I-albumin (~1,000 ng)
were divided into two portions and injected as a 500-µl bolus into
each lateral ventricle of conscious, awake sheep. Subsequently, serial
5-ml jugular venous blood samples and cervical and prescapular lymph
were collected every 0.5 h for a total period of 6 h. After 6 h, the
animal was euthanized (Euthanyl; MTC Pharmaceuticals, Cambridge, ON)
and head and neck lymph nodes, superficial lymph nodes, and muscle,
fat, and skin control tissues were excised and weighed. Cortical tissue
was harvested from four sheep. The
125I-TNF- and
131I-albumin were measured in
tissue, lymph nodes, and 1-ml aliquots of blood plasma and lymph using
a LKB 1282CompuGamma CS LKB Wallace (Pharmacia, Turku, Finland).
To ensure that measured radioactivity was protein associated, a second
set of aliquots was assayed after precipitation with 10%
tricholoracetic acid. Non-protein-associated
125I-TNF- and
131I-albumin amounted to <1% of
the total radioactivity in any sample.
Analysis of data. All results are expressed as means ± SD. Data were analyzed using ANOVA or paired Student's t-tests.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Recovery of
125I-TNF- and
131I-albumin in lymph
nodes. Six hours after the injection of
125I-TNF- and
131I-albumin into the lateral
ventricles, cervical, submandibular, preauricular, prescapular,
prefemoral, and popliteal lymph nodes and control tissues (skin,
skeletal muscles, and fat) were harvested and analyzed for
125I-TNF- and
131I-albumin
(n = 6). In comparison to peripheral
lymph nodes and control tissue,
125I-TNF- and
131I-albumin counts were elevated
in the deep cervical lymph nodes [F(1,5) = 18.95, P < 0.005, and
F(1,5) = 38.55, P < 0.002, respectively] (Fig.
1). Levels of
125I-TNF- and
131I-albumin recovered in the
cervical nodes were not statistically different. Lymph nodes from the
animal's prescapular, prefemoral, and popliteal nodes contained
similar levels of radioactivity to the control tissues.
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Recovery of
125I-TNF- and
131I-albumin in blood and
lymph.
125I-TNF- and
131I-albumin were detected in the
cervical lymphatics and in the blood within the first 30 min after the
intracerebroventricular injection in five sheep and showed considerable
variability. For technical reasons, data were not obtained from the
sixth sheep. There was greater recovery of
125I-TNF- and
131I-albumin in 1 ml of cervical
lymph compared with 1 ml of blood plasma
[F(1,4) = 21.27, P < 0.01, and F(1,4) = 218.86, P < 0.0005, respectively] (Fig.
2, A and
B).
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Recovery of
125I-TNF- and
131I-albumin in the
brain. Six hours after the intracerebroventricular
injection, cortical tissue was excised and sampled for
125I-TNF- and
131I-albumin to determine the
proportion of tracers remaining in the brain. The recovery of
125I-TNF- from the cortex was
2.10 ± 0.69 times greater than that of
131I-albumin.
TNF- induces SWS. After the
intracerebroventricular injection of 500 ng of TNF-, enhanced SWS
was observed in four sheep during the 6-h recording period
[F(1,3) = 4.57, P < 0.01] in comparison to the
sheep injected with aCSF. More specifically, SWS was significantly increased during the fourth and fifth hour postinjection
(P < 0.05)
(t-tests with a Bonferroni correction)
(Fig. 3, A
and B). Furthermore, sheep injected
with TNF- spent more time in a recumbent position
[F(1,3) = 8.47, P < 0.01]. TNF- did not
induce any changes in the total time the sheep spent in the drowsy
state or in REM sleep.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This work demonstrates a novel pathway for communication of
immunomodulatory substances between the brain and the peripheral immune
system. The results clearly show that radiolabeled TNF- introduced
into the CSF is recovered in the cervical lymph, in addition to the
blood. Radiolabeled TNF- appeared in cervical lymph more rapidly and
in greater concentration than in other lymphatic sites or in the blood.
The elevated recovery of
125I-TNF- and
131I-albumin in the nodes of the
head and neck region compared with other lymph nodes and tissues
indicates that the cervical lymphatic pathway received CSF draining
from the brain (3, 4, 7). It is unlikely that significant tracer
diffused from the blood into the lymphatics. If this were true, one
would expect to recover similar amounts of
125I-TNF- and
131I-albumin in both the cervical
and prescapular lymphatics. Furthermore, there were higher
concentrations of 125I-TNF- in
the cervical lymph compared with jugular venous blood.
The reduced recovery of
125I-TNF- compared with
131I-albumin in the lymph and in
the blood may be the result of TNF- sequestered in the brain. TNF
receptors are found in the brain stem, thalamus, basal ganglia, and
cortex regions, as demonstrated by Kinouchi et al. (19). In support of
TNF- remaining in the brain, our data show a higher residual
concentration of radiolabeled TNF- compared with albumin in the
brain tissue 6 h postinjection. Our description of TNF- being
retained in the brain is in agreement with others. Gutierrez et al.
(14) showed that the efflux of TNF- based on a half-time
disappearance rate from the brain was slower than would have been
predicted based on reabsorption of CSF, suggesting that TNF is
sequestered in the brain.
Sheep are alleged to be diurnal animals (28). However, actigraphy
studies show that sheep rest-activity patterns vary depending on the
environmental conditions. Sheep confined to a pen are less active and
have more daytime rest episodes than sheep that live in stalls or are
allowed to roam free in the field (28). Continuous electroencephalogram
(EEG) recordings in sheep confined to a metabolic cage showed that
sheep have ~4 sleep hours in each 24-h period. Sheep predominantly
slept during the night; however, sleep was also exhibited during the
day (25). In a preliminary study we examined sleep-wake behavior in two
sheep over 16-h and 24-h periods. Continuous baseline EEG recordings
showed that each sheep exhibited 23% SWS and 2% REM sleep in the
experimental period. SWS and REM sleep were randomly distributed
throughout the day and occurred in both the light and the dark period.
It is likely that the sheep's laboratory environment resulted in the
absence of circadian rhythmicity in the sleep-wake cycle. Therefore, we
were not able to address the interaction of TNF- on circadian
patterns of sleep EEG in sheep.
Our data show that TNF- induced SWS in sheep along with increased
time spent in a recumbent position. This is in agreement with the work
of Shoham et al. (26) and Kapas et al. (18), who both demonstrated that
TNF- induced SWS in rabbits. In our study, TNF- induced a
significant increase in SWS between 4 and 5 h postinjection, whereas
both Shoham et al. (26) and Kapas et al. (18) saw an increase in SWS 2 h postinjection. The delay in the sleep response in the sheep could be
a result of species specificity in the biochemical cascade that is
involved in sleep regulation. These data contribute to the existing
literature that TNF- is a sleep-regulating substance.
It is known that TNF- receptors (19), protein (12), and mRNA (5, 15)
are found in many areas of the brain, including the regions of the
anterior hypothalamus and the hippocampus. TNF- protein and mRNA in
the brain follow a diurnal rhythm, being 10-fold greater during non-REM
sleep in the rat (12). Plasma TNF- levels correlate with EEG delta
frequency amplitude in healthy humans (8) and are elevated during sleep
deprivation (29). Furthermore, central inhibition of TNF blocks sleep
rebound after sleep deprivation (27), and knockout mice lacking the
TNF- 55-kDa receptor show less non-REM sleep than control mice (10).
It is possible that the drainage of TNF- and other cytokines from
the brain into the lymphatics and into the blood may be one mode by
which the sleep-waking brain modulates peripheral immune function that
is involved in host defense mechanisms. TNF- is a potent
immunomodulator. Local injection of TNF- reduces lymphocyte output
from lymph nodes and alters the migration of lymphocyte traffic through
subcutaneous lymph nodes (30). Moreover, our findings have implications
for several pathological conditions, including multiple sclerosis (22),
trauma (9), and meningitis (24), in which TNF- levels are elevated
in the CSF. This pathway has the potential to affect peripheral immune
activity in these diseases that affect the CNS.
In summary, radiolabeled TNF- introduced into the CSF not only
induces sleep but is also recovered in the cervical lymphatics and in
the blood. This connection from the brain to the periphery provides the
possibility for the continual outflow of immunogenic material and
immune cells from the CNS to the extracerebral immune organs. These
pathways allow for highly regulated communication between the brain and
the immune system in both health and disease. The functional
implications of the drainage of cytokines from the CNS to the
peripheral immune system remain to be determined.
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ACKNOWLEDGEMENTS |
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We thank D. A. Homonko for thoughtful discussion and critical review of the manuscript and M. Boulton and T. Seabrook for technical assistance.
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FOOTNOTES |
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This study was supported by the Toronto Psychiatric Research Foundation.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. B. Dickstein, Centre for Sleep and Chronobiology, 019-3D, 399 Bathurst St., Toronto, ON, Canada M5T 2S8 (E-mail: jodi.dickstein{at}utoronto.ca).
Received 20 October 1998; accepted in final form 22 December 1998.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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, TNF-
, aCSF. Injections were done at
time
0. Sleep values are hourly averages.
* Statistical difference using paired Student's
t-test with Bonferroni correction.