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gene
,1
,12
* Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan;
Gifu Research Laboratory, JBC, Inc., Gifu 503-0628, Japan;
Department of Laboratory Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan;
§ Laboratory of BioOrganic Chemistry, NIDDK, Bethesda, Maryland 20892, USA; and
¶ Department of Immunology, National Institute of Animal Health, Tsukuba 305-0856, Japan
2Correspondence: K.Saito, Department of Laboratory Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan. E-mail: saito{at}cc.gifu-u.ac.jp; or T.N., Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan. E-mail: tnabeshi{at}.med.nagoya-u.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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increase in many inflammatory conditions,
including HIV-1 infection, and may contribute to neurodegenerative
processes. The paucity of agents that can selectively and potently
block TNF- processing or its receptors has led us to investigate the
role of TNF- in chronic neurodegeneration associated with retroviral
infection using mice with targeted deletions of the TNF- gene.
Infection of wild-type C57BL/6 mice with the LP-BM5 murine leukemia
retrovirus mixture leads to the development of a severe
immunodeficiency as well as cognitive deficits and neuronal damage.
TNF--(-/-) mice infected with LP-BM5 developed a systemic
immunopathology indistinguishable in severity from that observed in
contemporaneously infected wild-type mice. In contrast, the performance
of infected TNF--(-/-) mice in the Y-maze and Morris water maze was
not different from that of uninfected TNF--(-/-) mice. The extent of
glial activation in the striatum, as indicated by the increase in
density of peripheral benzodiazepine receptors, was equivalent in both
groups of LP-BM5-infected mice. However, the decrease in striatal MAP-2
expression, a marker of neurodegeneration observed in infected
wild-type mice, was not found in infected TNF--(-/-) mice. While the
loss of TNF- appeared to have no effect on the course or severity of
the central or peripheral immunopathology resulting from LP-BM5
infection, the behavioral and biochemical manifestations were
substantially curtailed in the TNF--(-/-) mice. These findings
directly support a role for TNF- in the neurodegenerative processes
associated with viral infections such as HIV-1.—Iida, R., Saito,
K., Yamada, K., Basile, A. S., Sekikawa, K., Takemura,
M., Fujii, Wada, H. H., Seishima, M., Nabeshima, T. Suppression of
neurocognitive damage in LP-BM5-infected mice with a targeted deletion
of the TNF- gene.
Key Words: animal model • AIDS • TNF--(-/-) mice • dementia • learning • behavior
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(TNF-) is a
proinflammatory cytokine produced outside the central nervous system
(CNS) by macrophages and circulating monocytes, and inside the brain by
microglia (1
2
3)
. In the CNS, TNF- elicits many
behavioral and physiological changes, including hypophagia, pyresis,
hypothalamic-pituitary-adrenocortical axis (HPA) activation, and
inflammatory responses (2)
. Brain TNF- levels are
typically elevated after trauma (4)
and ischemia
(5)
, and in response to viral and bacterial infections
(1
, 6)
. Although there is evidence that the actions of
TNF- may serve to protect the brain by promoting astrocytosis
(7)
, activating NF-
B (8)
, stimulating
antioxidant pathways (9)
, and limiting the course of the
inflammatory response (2)
, TNF- also damages CNS
elements through direct and indirect mechanisms. These pathogenic
effects include oligodendroglial toxicity and demyelination
(7
,10)
, resident microglial activation (11)
,
disruption of the blood-brain barrier (12)
, and
excitotoxic neuron damage (13
, 14)
.
One of the clinically relevant states where TNF- induction may play
a prominent neuropathologic role is in the development of human
immunodeficiency virus (HIV)-associated dementia complex (HADC)
(15
, 16)
. The adult CNS is invaded by HIV-1 early in the
course of infection and may give rise to an encephalitis characterized
by HIV-1-positive macrophage infiltrates, gliosis, focal demyelination,
and neuronal damage (17)
. These lesions are found
primarily in the frontal and parietal subregions of the cerebral
cortex, the caudate, and putamen (17)
. The neurological
manifestations of HADC are typically observed in the later stages of
infection, when peripheral virus load increases, and CD4-positive cell
count declines (18)
. Although the spectrum of mechanisms
involved in the pathogenesis of HADC remains unclear, one route
involves the local production of proinflammatory cytokines including
TNF- (15
, 19)
.
The role of TNF- in the CNS inflammatory processes associated with
chronic retroviral infections may be investigated in mice infected with
the murine leukemia retrovirus mixture LP-BM5. Mice infected with
LP-BM5 develop a profound immunodeficiency, characterized by impaired
T- and B-cell responses to mitogens, polyclonal B-cell activation,
hypergammaglobulinemia, enhanced susceptibility to secondary
infections, and the emergence of lymphoma secondary to the development
of anergy (20)
. By 3 wk after infection, microglial
activation is observed, particularly in the striatum, where highly
activated microglial nodules develop (21)
. This is
followed at 5-wk postinfection by foci of activated astrocytes,
particularly in the cortex and striatum. By 8-wk postinfection,
biochemical evidence of altered neuronal function is observed, with
significant decreases in the levels of neurotransmitters in the
striatum, hypothalamus, and cerebral cortex (22)
, and
alterations in second messenger systems (23
, 24)
.
Histological evidence of neuronal damage in the striatum and cortex is
evident by 10–12-wk postinfection (25)
, concurrent with
deficits in learning and memory (26
, 27)
. Administration
of pentoxyfylline was previously found to reduce the immunosuppression
and neuronal damage developed by LP-BM5-infected mice (28)
(Y. Sei and A. S. Basile, unpublished observations). However, it
was not clear if this resulted from the ability of pentoxyfylline to
alter cAMP phosphodiesterase activity or by suppressing TNF-
production. Thus, the role of TNF- in neurodegeneration associated
with chronic, retrovirus-induced encephalopathies may be more directly
observed in LP-BM5-infected mice with targeted deletions of the TNF-
gene.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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gene
. Congenic C57BL/6-TNF--(-/-) and C57BL6 mice were
used in the present experiment. Briefly, TNF-KO mice derived from TT2
ES cell line (established from C57BL/6 x CBA/JNCrj Fi blastocyte)
were backcrossed to C57BL/6 more than eight generations
(30)
. Homozygous TNF--(-/-) were obtained by
interbreeding of heterozygotes and confirmed by Southern blot analysis
for TNF- allele. H2 haplotype of TNF--KO mice was determined to
be H2b, same as C57BL/6, by Dr. Iwakura
(Institute for Medical Science, The University of Tokyo). The animals
were housed in groups of 10 in a temperature-, humidity-, and
light-controlled room (23±1°C, 50±5% humidity, 12-h light cycle,
starting at 8:00 a.m.), and had free access to food and water, except
during the behavioral experiments.
LP-BM5 infection
Mice 4–6 wk of age were infected by intraperitoneal (i.p.)
injection of 0.2 ml of LP-BM5 murine leukemia retrovirus mixture
prepared from the G6 clone of chronically infected SC-1 cells
(31)
. Control groups of mice were injected with 0.2 ml of
culture media from uninfected SC-1 cells.
Determination of cell-surface antigens by flow cytometry
The progression of LP-BM5 infection was assessed by flow
cytometric analysis of splenocytes labeled with monoclonal antibodies
against CD4, CD8, B220, and IL-2Rß (PharMingen, San Diego, Calif.)
(32)
. Mean fluorescence intensity and the percentages of
antigen-positive and -negative cells were acquired on a flow cytometer
(FACS scan, Beckton Dickinson Immunocytometry Systems, Palo Alto,
Calif.) and analyzed by LYSIS II software. A total of 10,000 events was
analyzed for each antigen.
Splenocyte responses to mitogens
Splenic T- and B-cell responses to mitogens were determined by
[3H]-thymidine incorporation (32)
.
Spleen cells (1 x 105 cells/200 µl/well)
were cultured in 96 well plates with RPMI 1640 medium (supplemented
with 10% heat-inactivated fetal-bovine serum, 100 units/ml penicillin,
and 100 µg/ml streptomycin). The splenocytes were then stimulated
with either concanavalin A (Con A) (2 µg/ml) or lipopolysaccharide
(LPS) (10 µg/ml) for 48 h, followed by a pulse of
[3H]-thymidine (0.2 µCi/well, New England
Nuclear, Boston, Mass.). [3H]-Thymidine
incorporation into the splenocytes after 12 h of incubation was
determined by liquid scintillation counting (32)
.
Y-maze test
Spontaneous alternation behavior of mice in a Y-maze, an index
of short-term memory, was measured 10 wk after the infection with
LP-BM5 (33
, 34)
. The maze was made of black painted wood,
with each arm 40 x 10 x 12 cm (L x W x H),
tapering to 3-cm wide at the bottom. The arms converged to a triangular
center, 4 cm per side. Each mouse was placed at the end of an arm and
allowed to move freely throughout the maze during an 8-min session. The
series of arm entries was recorded visually. Alternation was defined as
successive entry into the three arms on overlapping triplet sets. The
percent alternation was calculated as the ratio of actual alternations
to possible alternations (defined as the total number of arm entries
minus two), multiplied by 100.
Water maze tests
Water maze tests were performed on mice 12–15 wk after LP-BM5
infection in a pool 1.2 m in diameter constructed from white
polypropylene (33
, 35)
. Water temperature was maintained
at 18 ± 1°C.
In the acquisition test, the Plexiglas platform (7 cm in diameter) was submerged 2 cm below the water surface level and maintained in the same location throughout the training period. Swimming paths were tracked with a camera fixed on the ceiling of the experimental room and stored in a computer (TARGET/2 system, Neuroscience, Tokyo). Three starting positions were used pseudorandomly, and the mice were trained to escape onto the submerged platform using three trials per day for 10 days. Each trial lasted 60 s (criterion time). If the mouse found the platform, it was allowed to remain for 20 s before being returned to its home cage. If the mouse was unable to find the platform within 60 s, the training was terminated, and a maximum score of 60 s was assigned.
The probe test was performed one day after the last training trial. In this test, the platform was removed, and each mouse was placed into the pool for 60 s. The total time spent in the quadrant, which had contained the platform during the training trials, was measured.
[3H]PK-11195 binding
After behavioral testing, the mice in all groups were killed
according to AAALAC guidelines. The brains were rapidly removed,
dissected on wet ice, frozen on dry ice, and stored at –70°C until
used. Brain regions were homogenized in 50 volumes of 50 mM Tris HCl
buffer, pH 7.4, with a Polytron (30 s, setting 6), washed by
centrifugation at 20,000 g for 20 min at 0–4°C, and the
pellet was finally resuspended in 20 volumes of buffer
(36)
. The assay was performed in duplicate in glass test
tubes by incubating 300 µl aliquots of homogenate with 50 µl of
[3H]PK-11195 (0.5–20 nM final concentrations,
New England Nuclear) in either the presence or absence of 10 µM Ro
5–4864 for the determination of nonspecific binding. Sufficient buffer
was added to yield a final volume of 0.5 ml. After 1 h of
incubation at room temperature, the assay was terminated by rapid
filtration over glass fiber filters (#32, Schleicher and Schuell,
Keene, N.H.) pretreated with 0.03% polyethylenimine. The filters were
placed into vials with scintillation fluid (Cytoscint, ICN Biomedical,
Aurora, Ohio), and the radioactivity retained counted for 2 min
(LS6500, Beckman, Fullerton, Calif.). The equilibrium binding constants
were determined by data analysis using nonlinear regression techniques
(Prism II, GraphPad Software, San Diego, Calif.).
Microtubule-associated protein-2 (MAP-2) immunoblots
Samples were harvested as above and subsequently homogenized by
10 s of sonication in 10 volumes of 0.32 M sucrose/10 mM Tris HCl
(pH 7.4) with a protease inhibitor mixture (Calbiochem, San Diego,
Calif.) (25)
. The homogenates were incubated at 0–4°C
for 30 min, then centrifuged at 20,000 g for 30 min. A
50-µl aliquot of supernatant was mixed with 50 µl of goat antimouse
IgG coupled to agarose beads (Sigma Chemicals, St. Louis, Mo.), and the
mixture was shaken for 12 h at 0–4°C. The beads were removed by
centrifugation at 1500 g for 10 min, and the protein content
of the supernatant was measured (bicinchoninic acid technique, Pierce
Chemicals, Rockford, Ill.). Aliquots of the supernatant containing 35
µg of total protein were mixed with denaturing loading buffer and
loaded onto 4–12% gradient polyacrylamide gels. The proteins were
separated at 125 volts in constant voltage mode, then transferred to a
PVDF membrane, which was incubated with the primary antibody to MAP-2
(1:1000, monoclonal mouse anti-MAP-2, HM2, Sigma) with agitation for 2
days at 0–4°C. The membranes were rinsed three times in
I-Block/phosphate-buffered saline/0.05% TWEEN-20 solution, incubated
for 1 h with alkaline phosphatase-conjugated goat anti-mouse IgG
(Kirkegaard & Perry Laboratories, Gaithersburg, Md.) for 1 h at
25°C, then developed with an enhanced chemiluminescence protein
immunodetection system (Tropix, Bedford, Mass.).
Optical density measurements were made by acquiring digitized images with shading correction. The optical density of each image was determined by converting the gray scale values to absolute optical density units using a calibrated film scale. The data were then presented as percent of O.D. values taken from corresponding control samples run on the same gel.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-(-/-) and wild-type mice at 10-wk postinfection was assessed by
weighing the spleen, liver, and lymph nodes, and determining the
surface phenotype and proliferative responses of splenocytes in
response to Con A and LPS. Marked splenomegaly, hepatomegaly, and
lymphoproliferation were observed in both TNF--(-/-) and wild-type
mice, with no significant differences between the two groups of
infected mice (Table 1
). Both TNF--(-/-) and wild-type mice showed a significant—98.7%
and 98.9%; and 89.8% and 90.5%—suppression of the proliferative
response to Con A and LPS, respectively (Table 1)
. The extent of
disease progression in LP-BM5-infected mice was further assessed by
determining the percentages of B220-positive, CD4-positive, and
interleukin-2 receptor ß (IL-2Rß)-positive cells, and the ratio of
CD4/CD8-positive cells in infected TNF--(-/-) and wild-type mice at
10-wk postinfection. The percentage of B220-positive B cells decreased
16.8% and 11.9% (P<0.05, infected wild-type, infected
TNF--(-/-), respectively, Fig. 1A
) after injection, and the percentage of CD4-positive and
IL-2Rß-expressing T cells in both infected mouse groups increased
2.7- and 3.8-fold above uninfected mouse levels (P<0.05,
Fig. 1B
). Moreover, the CD4/CD8-positive cells ratio was
increased 3.8- and 2.5-fold in the infected vs. uninfected mouse groups
(P<0.05, Fig. 1C
). There were no significant
differences between the two infected groups of mice in these indices.
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The mnemonic abilities of LP-BM5-infected mice were tested by measuring
spontaneous alternation behavior in the Y-maze and performance in the
Morris water maze. Spontaneous alternation behavior by infected
wild-type mice was significantly decreased compared with control
(P<0.05, Fig. 2A
). However, infected TNF--(-/-) mice showed performance
levels that were not different from uninfected TNF--(-/-) mice (Fig. 2A
). The total number of arm entries, an index of
exploratory activity, was significantly decreased by 85.8% in
LP-BM5-infected wild-type mice compared with the control wild-type
group (P<0.01, Fig. 2B
). In contrast, the number
of arm entries for both the infected and uninfected TNF--(-/-)
groups was decreased relative to uninfected wild-type mice and to the
same extent (68.8, 63.7%).
|
Spatial reference learning and memory were tested in the Morris water
maze (37)
. The escape latency was significantly prolonged
on sessions 5, 7, and 9 of acquisition training in the LP-BM5-infected
wild-type mice compared with uninfected wild-type mice (Fig. 3A
). However, there was no difference in escape latency
between infected and control TNF--(-/-) mouse groups, nor between
these two groups and control wild-type mice. Furthermore, there was no
difference among the four groups in their swimming speed (Fig. 3B
). In the probe test, one day after the last training
trial in which the platform was removed from the pool, LP-BM5-infected
wild-type mice spent 50% less time (P<0.01, Fig. 3C
) within the platform-quadrant compared with uninfected
wild-type mice. There was no difference in time spent within the
platform-quadrant between infected and control TNF--(-/-) groups or
control wild-type (Fig. 3C
).
|
The degree of microglial activation in the striatum and cerebral cortex
was assessed in these mice by quantifying the density of peripheral
benzodiazepine receptors using [3H]PK-11195
binding (38
, 39)
. The affinity (Kd) of
[3H]PK-11195 for the peripheral benzodiazepine
receptor was not altered in brain regions from any of the mouse groups
(ranging from 1.09±0.13 to 1.43±0.14 nM). In contrast, the density
(Bmax) of [3H]PK-11195 binding was
significantly increased by 1.7- to 2.5-fold in the striata from both
infected groups of mice (Fig. 4A
). Although there was a trend toward an increase in the Bmax
for [3H]PK-11195 binding to the cerebral cortex
in infected mouse groups, the difference between the infected and
control wild-type groups did not reach significance (1600±125 vs.
2300±500 fmol/mg protein, respectively).
|
The extent of neuronal dendritic damage was assessed by measuring
changes in MAP-2 immunoreactivity (25
, 40)
. Although
cortical MAP-2 immunoreactivity was marginally decreased in
LP-BM5-infected wild-type mice, MAP-2 immunoreactivity in the striatum
was significantly reduced by 75% of the control levels. In contrast,
no changes in striatal or cortical MAP-2 immunoreactivity were observed
in infected TNF--(-/-) mice (Fig. 4B
, 4C
).
|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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commonly
occur in the brain under conditions of chronic inflammation, as in
patients with HIV-1 infection and HADC (15
, 16
, 19)
.
Evidence suggests that TNF- may contribute to the neuronal and
oligodendroglial damage observed in patients with HIV-1 infection and
other CNS disorders. This premise is supported by studies of transgenic
mice, which chronically overexpress TNF- and develop chronic
inflammatory demyelination and severe neurological deficits
(10)
. Recent studies of the potential neuroprotective
actions of TNF- (8
, 9)
have added to the difficulty in
delineating the role(s) that TNF- plays in inflammatory
neurodegeneration in vivo. In part, this is because the
paucity of agents can selectively block the actions of TNF-, and the
unexpected role of TNF receptors (TNF-R) in lymphoid organogenesis
(41)
may influence studies using mice with targeted
deletions of the TNF-R. Using mice with a targeted deletion of the
TNF- gene coupled with a model of retroviral encephalopathy (LP-BM5
murine leukemia virus) may constitute a more direct route for
addressing the role of TNF- in chronic retroviral encephalopathies.
Wild-type mice infected with LP-BM5 typically show a significant
increase in the expression of TNF- mRNA by splenocytes, beginning at
4-wk postinfection and steadily increasing throughout the course of the
infection (42)
. Despite the lack of TNF- in
LP-BM5-infected TNF--(-/-) mice, there was no evidence that the
course or severity of the infection had been altered, as indicated by
the lack of difference in lymphoid organ weight or the proportion of B-
and T-cell subpopulations between the infected TNF--(-/-) and
wild-type mice. This contrasts with the acceleration of lymphadenopathy
observed in lpr mice lacking the TNF-R1 (43)
.
The lack of change in the course and virulence of the underlying virus
infection and accompanying immunopathology, despite the absence of
TNF-, suggests that the TNF--(-/-) mice have compensated for the
loss of immunoregulatory functions directed by TNF-. Although the
course of the infection was not apparently altered, significant changes
in behavior and neurochemistry were exhibited by the infected
TNF--(-/-) mice.
Typically, substantial decrements in the performance of learning and
memory tasks are displayed by wild-type C57BL/6 mice by 8–10 wk after
infection with LP-BM5 (26
, 27
, 33)
. Similarly, performance
of LP-BM5-infected wild-type mice in the Y-maze was measurably impaired
in the present study. However, there was absolutely no difference in
Y-maze performance between the infected and uninfected TNF--(-/-)
mice, whose performance paralleled that of the uninfected wild-type
mice. Infected wild-type mice were also slower in learning to escape
the Morris water maze, typically showing place acquisition impairment,
thigmotaxis and spatial bias for the target quadrant, behaviors
consistent with striatal lesions (44)
. None of these
deficits were observed in LP-BM5-infected TNF--(-/-) mice. Moreover,
these performance deficits were not an artifact of impaired motor
function, because the swimming speed of all mouse groups was the same.
There was some evidence of anxiety displayed by the infected wild-type
mice and both groups of TNF--(-/-) mice. Although this may reflect
sickness behavior in the infected wild-type group, the expression of
anxiety and fearfulness behaviors has been previously observed in mice
with targeted deletions of cytokines (45)
and other
receptor systems (46)
. Thus, it is unlikely that the
change in arm entries displayed by the TNF--(-/-) groups reflects a
neurodegenerative process associated with LP-BM5 infection, nor did it
appear to influence performance in the water maze.
The development of spatial learning and memory deficits in
LP-BM5-infected mice is preceded by inflammation in the CNS and
neurodegeneration (21
, 22
, 25)
. Cytokines and virus
proteins in the blood during the initial viremia probably caused the
profound microglial activation occurring at 3 wk after infection. Some
activated microglia in the striata of infected wild-type mice also show
immunohistochemical evidence of TNF- expression (Y. Kustova,
personal communication). This microglial activation is followed by
localized astrocytosis, increased production of neurotoxins such as
glutamate and platelet-activating factor (47
, 48)
,
neurotransmitter loss, and dendritic deafferentation (21
, 22
, 25)
, particularly in the striatum and the cerebral cortex. The
activation of microglia in vivo by TNF- can be manifested
as an increase in the density of peripheral benzodiazepine receptors
(38
, 49)
. Wild-type mice infected with LP-BM5 showed
striatal and cortical microglial activation, as indicated by the
increase in Bmax for [3H]PK-11195 binding.
Similar densities of [3H]PK-11195 binding were
observed in the brains of infected TNF--(-/-) mice, further
indicating that the loss of TNF- does not substantially alter the
immune response (microglial activation) to this virus infection.
However, evidence of neuronal damage, which commonly occurs after glial
activation in infected wild-type mice and is sensitively indicated by a
decrease in dendritic MAP-2 immunoreactivity, was not observed in the
infected TNF--(-/-) mice.
Numerous studies support a dual role for TNF- in orchestrating
inflammatory processes, first by enhancing proinflammatory responses
and later by acting as an antiinflammatory agent. In the brain, this
may be manifested as an initial activation of microglia (11
, 50)
, suppression of glutamate uptake (14)
, and
oligodendroglial damage (10)
, followed by a decreased
responsiveness of glutamate receptors and suppression of oxidative
stress (8
, 9)
. This latter, neuroprotective function may
be manifested in acute inflammatory episodes (infarcts, seizures,
trauma), which can be resolved over a period of weeks or a few months.
However, in chronic inflammatory conditions, such as retroviral
encephalopathy (e.g., HADC) or encephalomyelopathy (e.g., multiple
sclerosis), the resolution phase with its neural protective aspects may
be significantly delayed in onset. The present data from an animal
model of retroviral encephalopathy support a major role for TNF- in
causing or promoting neuronal damage leading to cognitive deficits as a
result of such open-ended or recurrent inflammatory processes. Thus,
therapeutic modalities, which suppress TNF- expression or activation
of its receptors in chronic CNS inflammatory states, may substantially
protect neurons and oligodendroglia without significantly curtailing
important immune functions.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
Received for publication August 16, 1999. Revised for publication December 16, 1999.
|
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