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The Journal of Neuroscience, September 15, 2001, 21(18):7046-7052
Interleukin-1 Promotes Repair of the CNS
Jeffrey L.
Mason1,
Kinuko
Suzuki2,
David D.
Chaplin4, and
Glenn K.
Matsushima1, 3
1 Curriculum in Neurobiology and the University of
North Carolina Neuroscience Center, 2 Department of
Pathology and Laboratory Medicine, and 3 Department of
Microbiology and Immunology, and the Program of Molecular Biology and
Biotechnology, University of North Carolina, Chapel Hill, North
Carolina 27599, and 4 Department of Internal Medicine and
Howard Hughes Medical Institute, Washington University School of
Medicine, St. Louis, Missouri 63110
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ABSTRACT |
Interleukin-1 (IL-1) is a proinflammatory cytokine associated
with the pathophysiology of demyelinating disorders such as multiple
sclerosis and viral infections of the CNS. However, we demonstrate here
that IL-1 appears to promote remyelination in the adult CNS. In
IL-1 / mice, acute demyelination
progressed similarly to wild-type mice and showed parallel mature
oligodendrocyte depletion, microglia-macrophage accumulation,
and the appearance of oligodendrocyte precursors. In contrast,
IL-1/ mice failed to remyelinate
properly, and this appeared to correlate with a lack of insulin-like
growth factor-1 (IGF-1) production by microglia-macrophages and
astrocytes and to a profound delay of precursors to differentiate into
mature oligodendrocytes. Thus, IL-1 may be crucial to the repair of
the CNS, presumably through the induction of astrocyte and
microglia-macrophage-derived IGF-1.
Key words:
oligodendrocytes; astrocytes; microglia; remyelination; cytokines; growth factors
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INTRODUCTION |
Metabolic, toxic, or autoimmune
insult of the adolescent and adult CNS may lead to the depletion of
mature oligodendrocyte population within the lesion during
demyelination (Blakemore, 1973 ; Yagima and Suzuki, 1979; Yao et al.,
1995; Gensert and Goldman, 1997; Mason et al., 2000a). Consequently, an
alternative source of oligodendrocytes most likely participates in the
remyelination. Several studies have identified differentiating
oligodendrocyte progenitors as the cells responsible for remyelinating
lesions within the adolescent (Ludwin, 1979) and adult (Gensert and
Goldman, 1997; Mason et al., 2000a) CNS. The factor(s) responsible for the recruitment and differentiation of these progenitors in
vivo has not been fully delineated.
One factor is a 17 kDa proinflammatory cytokine, interleukin-1
(IL-1) (Bauer et al., 1993; Sairanen et al., 1997), that is produced
primarily by microglia and macrophages (Giulian et al., 1986; Bauer et
al., 1993; Sairanen et al., 1997). This cytokine, in turn, induces the
production of IL-6 and tumor necrosis factor- , as well as nitric
oxide (for review, see Lee et al., 1995). It also induces the
proliferation of macrophages (Feder and Laskin, 1994) and astrocytes
(Giulian and Lachman, 1985; Giulian et al., 1988), both in
vitro and in vivo, but not oligodendrocyte progenitors in vitro (Merrill, 1991). In contrast, IL-1 has been
shown to be cytotoxic to mature oligodendrocytes in vitro
(Merrill, 1991; Brogi et al., 1997). Therefore, IL-1 has been
associated predominantly with exacerbating pathology in the CNS.
Repair of insult to the CNS has been increasingly attributed to immune
responses (Diemel et al., 1998; Schwartz et al., 1999; Warrington et
al., 2000). Along these lines, IL-1 may activate cells within the
CNS to produce growth factors known to induce the proliferation and
differentiation of oligodendrocyte progenitors in vitro
(Araujo and Cotman, 1992; Silberstein et al., 1996; Glazebrook et al.,
1998). One of these growth factors, insulin-like growth factor-1
(IGF-1), has been colocalized within demyelinating lesions of the CNS
(Komoloy et al., 1992; Liu et al., 1994; Yao et al., 1995) and shown to
parallel the accumulation and differentiation of oligodendrocyte
progenitors (Mason et al., 2000a). Furthermore, the early expression of
IGF-1 before morphologic demyelination protects mature oligodendrocytes
from cell death and promotes rapid repair of the lesion (Mason et al.
2000b).
To address the role of IL-1 in the remyelination process, we used a
model in which continuous cuprizone (bis-cyclohexanone oxaldihydrazone) intoxication of adult C57BL/6 mice leads to
perturbation and death of mature oligodendrocytes. This is followed by
massive demyelination in the corpus callosum by 5 weeks (Hiremath et
al., 1998; Morell et al., 1998; Mason et al., 2000a). Simultaneously, oligodendrocyte progenitors accumulate within the lesion beginning at
3-4 weeks and results in mature oligodendrocytes repopulation beginning at week 6, with remyelination occurring over the next 4 weeks
(Morell et al., 1998; Mason et al., 2000a, 2001). In this study, we
noted that IL-1 was upregulated in mice exposed to cuprizone and
used IL-1-deficient mice (Shornick et al., 1996) to examine the
functional importance of IL-1 in demyelination-remyelination.
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MATERIALS AND METHODS |
Induction of demyelination-remyelination.
IL-1/ mice on the
C57BL/6 background were bred in our mouse colony, and C57BL/6J (B6)
mice were purchased from The Jackson Laboratory (Bar Harbor, ME). At 8 weeks of age, the mice were fed a diet containing 0.2% cuprizone
(Sigma, St. Louis, MO) by weight, mixed into ground mouse chow for 6 weeks to induce demyelination (Hiremath et al., 1998). Subsequently,
mice were returned to a normal diet for another 6 weeks to allow
remyelination to occur. Sham and cuprizone-treated mice were
killed weekly. The forebrains from the mice were removed for
RNA, protein, and immunohistochemical analysis as described previously
(Mason et al., 2000a). All mice were maintained in accordance with
guidelines approved by the Institutional Animal Care and Use Committee
and the University of North Carolina Division of Laboratory Animal Medicine.
RNA analysis. Total RNA was prepared from half of the
forebrain of each mouse, reverse transcribed into cDNA, and then
amplified by PCR as described previously (Mason et al., 2000a).
Primer sequences used for the PCR reactions have been published
previously: IGF-1 (Shinar and McMorris, 1995) and IL-1 and
glyceraldehyde-3-phosphate dehydrogenase (G3PDH) (Bencsik et
al., 1996). Templates were denatured at 95°C for 5 min, followed by
30 cycles of denaturation (95°C for 1 min) primer annealing (62°C
for 1.5 min) and extension (72°C for 1 min), with a final extension
step at 72°C for 15 min. The amplified cDNA mixture of each sample
was separated on a 2.5% agarose gel containing ethidium bromide and
photographed. Amplification of the housekeeping gene G3PDH confirmed
RNA amplification and equal loading of each sample. The mRNA profiles
were semiquantitated using a densitometer to normalize all samples for comparison.
Immunohistochemistry. All comparative analyses were focused
in the corpus callosum on either side of midline in sections 220-260 of the mouse brain atlas (Sidman et al., 1971). The frozen
sections were stained for IL-1 (Endogen, Woburn, MA), IGF-1 (the
rabbit anti-IGF-1 antibody was a gift from Dr. Underwood, Chapel Hill, NC), and NG2 (the rabbit anti-NG2 antibody was a gift from Dr. William
Stallcup, San Diego, CA) as described previously (Mason et al.,
2000a).
In addition, adjacent sections were double-stained for GFAP, an
astrocyte marker (Santa Cruz Biotechnology, Santa Cruz, CA), and either
IL-1 or IGF-1, or sections were stained for CD11b (Mac-1), a
microglial-macrophage marker (PharMingen, San Diego, CA) and either
IL-1 or IGF-1. Tissue sections were incubated with rabbit anti-IGF-1
antibody and either goat anti-GFAP or biotin-conjugated rat anti-CD11b
antibody, or rabbit anti-IL-1 antibody and either goat anti-GFAP or
biotin-conjugated rat anti-CD11b antibody overnight at 4°C. The
GFAP-IGF-1 and GFAP-IL-1-labeled sections were then incubated with
biotin-conjugated horse anti-goat secondary antibody (Vector
Laboratories, Burlingame, CA). The GFAP-IGF-1, GFAP-IL-1, CD11b-IGF-1, and CD11b-IL-1-labeled sections were incubated with a
combination of a rhodamine-conjugated goat anti-rabbit secondary antibody (Vector Laboratories) strepavidin-fluorescein complex (Vector
Laboratories) before mounting with a coverslip. No positive cell stain
was observed in tissue sections incubated with control isotype-matched
antibodies (rabbit IgG, Vector Laboratories; goat IgG, Vector
Laboratories; or rat IgG2a, PharMingen) in place
of the primary antibodies. Positive-stained cells were quantified only
if a nucleus was observed.
Paraffin-embedded sections were labeled for the Pi isoform of
glutathione S-transferase (GST-Pi; a mature oligodendrocyte marker) or stained with Ricinus communis agglutin-1 (RCA-1;
marks microglia-macrophage) as described previously (Morell et al., 1998; Mason et al., 2000a).
Cell number quantification.
IL-1+,
IL-1+-GFAP+,
IL-1+-Mac-1+,
IGF-1+, NG2+,
RCA-1+, and
GST-Pi+ cells from three to four mice were
analyzed using a Nikon (Tokyo, Japan) Optiphot FXA microscope
with epifluorescence optics as described previously (Mason et al.,
2000a).
Electron microscopy. Tissue samples from the forebrain of 0, 5, and 10 week treated mice (n = 3) were processed for
electron microscopic analysis, and the cross-sections of the corpus
callosi were analyzed as described previously (Coetzee et al., 1996;
Dupree et al., 1998).
Protein analysis. Protein was extracted from half of a
frozen forebrain of the wild-type and
IL-1/ mice. The frozen
forebrains were homogenized and boiled in 1% SDS as described
previously (Coetzee et al., 1996). Protein concentrations were
determined using a protein assay kit (Bio-Rad, Hercules, CA) with
bovine serum albumin as the standard. Quantification of IGF-1 protein
levels were determined by radioimmunoassay as described previously (Ye
et al., 1996) using 20 µg of total protein.
Statistical analysis. Statistical comparisons were made
using a one-factor between-subjects ANOVA. Multiple comparisons among treatment groups were made with Tukey's test.
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RESULTS |
Expression of IL-1 precedes an increase in IGF-1 expression
The expression of IL-1 and IGF-1 mRNA during demyelination and
remyelination was analyzed from the forebrains of wild-type mice.
IL-1 mRNA levels, although undetectable in sham mice, was markedly
upregulated during cuprizone exposure (Fig.
1A). At week 3, there
was a dramatic increase in IL-1 that was sustained up to 6 weeks.
Thereafter, when cuprizone was removed from the diet at week 6 and
remyelination was allowed to proceed, IL-1 mRNA levels diminished to
control levels. The mRNA levels for IGF-1 followed the increased
expression of IL-1 (Fig. 1A), in which a low level
of IGF-1 was detected at week 3 followed by an increased expression
from week 4 through week 7 (1 week into the remyelination phase).
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Figure 1.
Expression of IL-1 during
demyelination-remyelination in wild-type mice. A,
Reverse transcription-PCR of RNA extracted from brains of mice at
weekly intervals was examined for IL-1 and IGF-1. Mice were exposed
to cuprizone for 6 weeks and allowed to recover. A representative
example of three time course experiments is illustrated.
B, The number of IL-1+ cells in the
corpus callosum at the level of the fornix. The mean and SEM bars
representing the number of IL-1+ cells per square
millimeter are plotted for the triplicate set of
samples.
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Microglia-macrophages and some astrocytes produce IL-1
A few IL-1+ cells began to
accumulate in the corpus callosum at 1 and 2 weeks compared with
untreated control mice (Figs. 1B,
2A). This number
dramatically increased and coincided with the progression of
demyelination at 3 weeks in wild-type mice (Figs. 1B,
2B). The peak in both the number of
IL-1+ cells and demyelination within
the corpus callosum between 4 and 5 weeks (Fig. 1B)
is temporally and spatially correlated with the dramatic accumulation
of IGF-1+ cells (see Fig.
6A) and NG2+
oligodendrocyte progenitors (Mason et al., 2000a) within the demyelinating lesion. Thereafter, a large number of
IL-1+ cells remained in the corpus
callosum during the remyelination process (Fig. 1B),
when mature oligodendrocytes begin to repopulate the lesion area (Mason
et al., 2000a).
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Figure 2.
Most microglia-macrophages and some
astrocytes express IL-1 during demyelination-remyelination in
wild-type mice. A, Few or no IL-1+ cells
are present in the untreated corpus callosum. B, A large
accumulation of IL-1+ cells begins at week 3 in the
medial region of the corpus callosum posterior to the fornix.
C-E, Representative sections demonstrating the
colocalization (arrows) of IL-1-expressing cells
(green-stained cells in C) to
nearly all of the Mac-1+ macrophages
(red-stained cells in D and overlaid in
E) in the corpus callosum at week 4. F-H, The colocalization (arrows) of a
few IL-1-expressing cells (green-stained cells
in F) to GFAP+ astrocytes
(red-stained cells in G and overlaid in
H) in the corpus callosum. Scale bar, 30 µm.
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The large accumulation of IL-1-expressing cells in the corpus
callosum of wild-type mice detected at week 3 (Fig.
2B) closely parallels the increased presence of
microglia-macrophages and astrocytes as reported previously (Hiremath
et al., 1998; Morell et al., 1998). Immunohistochemistry showed that
81% of the IL-1+ cells were
Mac-1+ microglia-macrophages at week 4, whereas the remainder were mostly astrocytes. Nearly all of
Mac-1+ microglia-macrophages (Fig.
2C-E) and only 49% of GFAP+
astrocytes colocalized with IL-1 expression, as demonstrated in
Figure 2F-H. These results suggest that
microglia-macrophages are the predominant cell type producing IL-1
during the peak stages of demyelination.
Demyelination and oligodendrocyte depletion progressed similarly in
both wild-type and IL-1/ mice
A similar number of GST-Pi+ mature
oligodendrocytes and myelinated axons (85.6 ± 4.8 vs 93.8 ± 2.3%, respectively) was observed in both untreated
IL-1/ and wild-type mice
(Figs.
3A,B,
4A,B,
5). During exposure to cuprizone, the
axons in the corpus callosum of
IL-1/ (4.2 ± 1.8%
myelinated) and wild-type (7.6 ± 2.1% myelinated) mice were
almost completely demyelinated at 5 weeks (Fig.
3C,D). Thus, IL-1 alone does not appear to
contribute to demyelination. Coinciding with this demyelination at 5 weeks was the accumulation of RCA-1+
microglia-macrophage within the lesion site in both
IL-1/ (3165 ± 127 per square millimeter) and wild-type (2949 ± 226 per
square millimeter) mice. In addition,
GST-Pi+ mature oligodendrocytes were also
depleted within the lesion in both wild-type and
IL-1/ mice at 5 weeks
(Figs. 4C,D, 5), as expected from our previous report (Mason et al., 2000). These results suggest that the absence of
IL-1 does not have a dramatic effect on the pathological processes induced by cuprizone exposure.
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Figure 3.
Representative electron micrographs of
the myelinated, demyelinated, and remyelinated axons in the corpus
callosum of wild-type and IL-1/ mice.
Almost all axons are myelinated in the corpus callosum of untreated
wild-type (A) and
IL-1/ (B) mice.
Negligible number of myelinated axons, corresponding to peak
demyelination, are present in the corpus callosum of 5 week treated
wild-type (C) and
IL-1/ (D) mice.
E, Wild-type mice show that a large portion of the axons
in the corpus callosum have remyelinated, but
IL-1/ mice show fewer remyelinated
axons at week 10 (F), 4 weeks after removal of
cuprizone. Scale bar, 1.2 µm.
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Figure 4.
GST-Pi+ mature oligodendrocytes
in the corpus callosum of wild-type and
IL-1/ mice during demyelination and
remyelination. GST-Pi+ mature oligodendrocytes in
the corpus callosum of untreated wild-type (A)
and IL-1/ (B)
mice at 0 weeks. Mature oligodendrocyte recovery of wild-type
(C) and IL-1/
(D) mice at 5 weeks of treatment. Recovery of
GST-Pi+ cells in the corpus callosum of wild-type
(E) and IL-1/
(F) mice at 10 weeks. G, The mean
and SEM bars representing the number of GST-Pi+
cells per square millimeter are plotted for the triplicate set of
samples. Scale bar, 50 µm. CC, Corpus callosum. The
white dashed line separates the corpus callosum and
fornix. *p < 0.005; **p < 0.0005.
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Figure 5.
The presence of NG2+ cells
during demyelination and remyelination in
IL-1/ mice. NG2+
oligodendrocytes accumulate in the corpus callosum of wild-type
(A) and IL-1-deficient
(B) mice after 5 weeks of cuprizone treatment. A
reduction in the number of NG2+ oligodendrocyte
progenitors (450 ± 30 cells/mm2) in the corpus
callosum was observed in wild-type mice (C) (only
stained cells with nuclei were counted). This was in
contrast to the continued presence of progenitors (703 ± 38 cells/mm2) in the corpus callosum of
IL-1/ mice after 1 week of recovery
after 6 weeks of cuprizone treatment (D). Scale
bar, 20 µm.
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Remyelination is dramatically reduced in the absence
of IL-1
A large number of axons in wild-type mice showed a substantial
recovery (67.1 ± 2.5%) from the demyelinating insult by 10 weeks, 4 weeks after cuprizone was removed from the diet (Fig. 3E). In contrast, there was a significant
(p < 0.0002) reduction in the number of
remyelinated axons (45.1 ± 1.6%) within the corpus callosum of
IL-1/ mice at 10 weeks
(Fig. 3F). Thus, IL-1 appears to play a prominent role in promoting the remyelination process.
Repopulation of the GST-Pi+ mature
oligodendrocytes is dramatically reduced in the absence of IL-1
We have shown previously that new oligodendrocytes repopulate the
corpus callosum and are presumably responsible for remyelinating the
demyelinated lesion (Mason et al., 2000a). The lack of proper remyelination in IL-1/
mice may be attributable to an inability of these mice to
regenerate new mature oligodendrocytes. After 5 weeks of exposure to
cuprizone, the GST-Pi+ mature
oligodendrocytes began to reappear within the demyelinated corpus
callosum of wild-type mice (Fig.
4C,E,G). However, in the absence of IL-1, there was a dramatic reduction in the number of
GST-Pi+ oligodendrocytes and a significant
delay in their reappearance within the corpus callosum at 7 (p < 0.0005) and 10 (p < 0.005) weeks (Fig. 4F,G). Thus,
IL-1 appears to facilitate the regeneration of the mature
oligodendrocyte population after a demyelinating insult.
NG2+ oligodendrocyte progenitor accumulation
occurs in the absence of IL-1
Failure of mature oligodendrocytes to adequately repopulate the
demyelinated corpus callosum in
IL-1/ mice warranted
examination of oligodendrocyte progenitors. A large number of
NG2+ progenitors accumulated within the
demyelinated corpus callosum at 5 weeks in both wild-type (734 ± 41 cells/mm2) and
IL-1/ (710 ± 78 cells/mm2) mice (Fig.
5A,B). During remyelination when
progenitors presumably differentiate into mature oligodendrocytes,
NG2+ progenitor cells were significantly
diminished (p < 0.004) in number (450 ± 30 cells/mm2) by week 7 in wild-type mice
compared with that observed in
IL-1/ mice (703 ± 38 cells/mm2) (Fig.
5C,D). Thus, although
NG2+ cells diminished in numbers
presumably by differentiating into mature oligodendrocytes during
recovery in wild-type mice (Fig. 4G), they appear to remain
as progenitors and are not able to mature in the absence of IL-1
and/or IL-1-derived factors.
IGF-1+ microglia-macrophages and astrocytes
accumulate during demyelination in wild-type mice
Very little IGF-1 protein or IGF-1+
cells were present in the corpus callosum during the first 2 weeks of
treatment (Fig.
6A,B). At 3 weeks, an increase in both IGF-1 protein levels and the number of
IGF-1+ cells was observed, and this was
consistent with the appearance of IGF-1 mRNA observed in Figure 1. The
amount of IGF-1 protein and the number of
IGF-1+ cells in the corpus callosum peaked
between 4 and 5 weeks, with a large number of
IGF-1+ cells remaining in the corpus
callosum throughout the remyelination process (Figs.
6A,B,
7A,C). Thus, elevated
numbers of IGF-1+ cells in the corpus
callosum correlates with increased levels of IGF-1 mRNA and IGF-1
protein.
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Figure 6.
The number of IGF-1+ cells and
amount of IGF-1 protein increase within a demyelinating corpus callosum
in wild-type mice but not in IL-1/
mice. A, The mean and SEM bars representing the number
of IGF-1+ cells per square millimeter in wild-type
mice is plotted for the duplicate set of samples
(*p < 0.001). B, The mean and SEM
bars representing the amount of IGF-1 protein within the corpus
callosum of wild-type and IL-1/ mice
is plotted for the triplicate set of samples. KO,
Knock-out.
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The accumulation of IGF-1+ cells parallels
the accumulation of microglia-macrophages and astrocytes in the
demyelinating corpus callosum as reported previously (Hiremath et al.,
1998; Morell et al., 1998). Figure
7E-J demonstrates
colocalization of IGF-1 to nearly all
GFAP+ astrocytes and to a subpopulation of
Mac-1+ microglia-macrophages. This
finding suggests that, not only are astrocytes capable of IGF-1
production, but microglia-macrophages also are responsible for
producing IGF-1 within the demyelinating lesion.
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Figure 7.
The absence of IGF-1+
astrocytes and microglia-macrophages during demyelination and
remyelination in IL-1/ mice.
IGF-1+ cells appear in the corpus callosum of
wild-type mice (A) but not in IL-1-deficient
mice (B) after 5 weeks of treatment.
IGF-1+ cells remain in the corpus callosum of
wild-type mice (C) undergoing remyelination but
are absent in IL-1-deficient mice (D) after 1 week of recovery after 6 weeks of cuprizone treatment.
E-J, Representative sections from wild-type mice
demonstrating the colocalization of IGF-1 to GFAP+
cells and Mac-1+ cells within the demyelinating
corpus callosum at 4 weeks. E-G, The colocalization
(arrows) of IGF-1+ cells
(green-stained cells in E) to
nearly all of the GFAP+ astrocytes
(red-stained cells in F and overlaid in
G) within the lesion. H-J, The
colocalization (arrows) of a few
IGF-1+ cells (green-stained
cells in H) to Mac-1+
microglia-macrophages (red-stained cells in
I and overlaid in J) within the
lesion. Scale bars: A-D, 20 µm; E-H,
10 µm.
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Lack of IGF-1-producing cells in the absence of IL-1
In contrast to wild-type mice, there was no increase in IGF-1
protein and no IGF-1+ cells detected
within a demyelinating corpus callosum at 5 weeks (Figs.
6B, 7B) or a remyelinating corpus callosum
at 10 weeks (Fig. 7D) in
IL-1/ mice. The lack of
IGF-1 expression in
IL-1/ mice is
attributable to a diminished IGF-1 mRNA transcription (J. L. Mason, unpublished observation). The lack of IGF-1 is not attributable to reduced numbers of microglia-macrophages, which accumulate similarly in the corpus callosum of wild-type and
IL-1/ mice, as described
above. Thus, IL-1 appears to be a critical factor in mediating the
production of IGF-1 during demyelination and remyelination. The
inability of the oligodendrocyte progenitors to differentiate properly
may be attributable to this absence of IGF-1.
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DISCUSSION |
Although the primary insult to oligodendrocytes is toxicity to
cuprizone, the proinflammatory role associated with IL-1 suggested that its absence in
IL-1/ mice during acute
demyelination would result in an ameliorated neuropathology. Our report
is contrary to the notion that IL-1 would exacerbate demyelinating
diseases. We demonstrate a number of molecular and biological events
relating IL-1 to the remyelination process. (1) IL-1 expression
appears to precede and then parallel the expression of IGF-1 during
demyelination and remyelination. (2) In the absence of IL-1,
demyelination, mature oligodendrocyte depletion, and the accumulation
of oligodendrocyte progenitors within demyelinating lesions progressed
similarly to wild-type mice. (3) IGF-1 protein and mRNA levels are not
elevated and IGF-1+ cells are not present
within lesions in mice deficient for IL-1. (4) The lack of IGF-1
within the lesions in
IL-1/ mice is not
attributable to the absence or reduced numbers of microglia-macrophages within the lesion. (5) IL-1 (and perhaps IGF-1) is important for normal regeneration of the mature
oligodendrocyte population from a normal pool of progenitors and for remyelination.
The expression of IL-1 in wild-type mice that were exposed to
cuprizone correlated with active demyelination and smaller axonal
caliber, microglia-macrophage accumulation, IGF-1 expression, and the
recruitment oligodendrocyte progenitors (Figs. 1, 2B, 6B, 7) (Hiremath et al., 1998; Morell et al., 1998;
Mason et al., 2000a, 2001). Our report of microglia-macrophages as the
predominant cell type expressing IL-1 is consistent with previous
investigations (Giulian et al., 1986; Bauer et al., 1993). We also
observed some IL-1-producing astrocytes, which both supports
(Giulian et al., 1986; Sairanen et al., 1997) and contradicts (Bauer et
al., 1993) previous observations concerning the ability of astrocytes
to produce IL-1. The data here suggest that microglia-macrophages are the predominant source of IL-1 and they appear to be a strategic cell type in the remyelination process.
Surprisingly, the absence of IL-1 did not prevent the depletion of
mature oligodendrocytes, presumably by apoptosis during the first 4 weeks into demyelination (Mason et al., 2000a), or myelin pathology.
Although cuprizone toxicity is believed to be the primary insult to
oligodendrocytes, it is thought that proinflammatory cytokines such as
IL-1 may exacerbate neuropathology. Indeed, demyelination appeared
similar in the presence or absence of IL-1 within the scoring area
of the corpus callosum; however, in the IL-1/ mice,
demyelination encompassed other more peripheral areas of the corpus
callosum (data not shown). This observation would suggest that IL-1
may be somewhat protective even during demyelination, which is contrary
to in vitro work citing that IL-1 is detrimental to
oligodendrocytes (Merrill, 1991). Furthermore, the typical accumulation of microglia-macrophages or oligodendrocyte progenitors after exposure to cuprizone, either as the result of progenitor migration from other areas of the brain and/or the proliferation and
activation of local progenitors (Mason et al., 2000a), is not dependent
on IL-1 (Fig. 5). This is consistent with previous in
vitro studies demonstrating the inability of IL-1 to induce the
proliferation or differentiation of oligodendrocyte progenitors (Merrill, 1991). However, IGF-1 can induce the differentiation of
oligodendrocyte progenitors into mature oligodendrocytes (McMorris et
al., 1986; McMorris and Dubois-Dalq, 1988; Mozell and McMorris, 1991).
Our data in this report, showing an apparent block in oligodendrocyte differentiation and perhaps mature oligodendrocyte survival during remyelination, is consistent with the lack of IGF-1 production that
correlates well with the absence of IL-1 (Mason et al., 2000a).
The absence of IL-1 appeared to have a profound effect on the
recovery of mature oligodendrocyte and remyelination in the CNS. There
is a reduction in the mature oligodendrocyte population between the
first (week 7) (Fig.
4C,D,G) and fourth (week
10) (Fig. 4E-G) week into recovery in the
IL-1/ mice compared with
that observed in the wild-type mice. Consequently, there is also a
significant reduction in the number of axons that were remyelinated in
the IL-1/ mice compared
with the wild-type mice at 10 weeks (Fig.
3E,F). Interestingly, there
was a delayed regeneration of a small population of mature
oligodendrocytes in the
IL-1/ mice at 10 weeks
(Fig. 4F,G), suggesting that
additional factors, whose expression is not dependent on IL-1, are
contributing to the delayed partial remyelination observed in these mice.
Our results are consistent with others in demonstrating the ability of
astrocytes to produce IGF-1 within demyelinating lesions (Komoly et
al., 1992; Liu et al., 1994; Yao et al., 1995). However, our work
showed for the first time that microglia-macrophages within
demyelinating lesions also produce IGF-1. Furthermore, it has been
shown previously that microglia-macrophages express an array of growth
factor mRNAs in vitro (Rappolee et al., 1988; Elkabes et
al., 1996), including IGF-1 mRNA (Arkins et al., 1993). This presence
of microglia-macrophage is associated with active myelination during
development (Hutchins et al., 1992; Ellison and de Vellis, 1995) and
with the ability of macrophages to induce myelin gene expression in
oligodendroglial cultures (Hamilton and Rome, 1994; Laughlin et al.,
1997). Our results fit well with the hypothesis that
microglia-macrophage may be acting to promote remyelination. By
producing IL-1, an induction of growth-promoting factors such as
IGF-1 may be fostering mature oligodendrocyte repopulation and
remyelination during a pathological insult within the CNS.
| |
FOOTNOTES |
Received Jan. 9, 2001; revised June 5, 2001; accepted June 14, 2001.
This work was supported in part by the Howard Hughes Medical Institute
(D.D.C.), National Institute of Neurological Disorders and Stroke
Grants NS35372 (G.K.M.) and NS24453 (K.S.), and National Multiple
Sclerosis Society Grant RG2754B (G.K.M.). We thank Clarita Langerman
for the preparation and sectioning of tissue for electron microscopy
and Dr. Robert Bagnell and Victoria Maden for their photographic
expertise at electron microscopy. We are grateful to Dr. Pierre Morell
for his comments regarding this manuscript. IGF-1 measurements were
conducted graciously by Drs. P. Ye and J. D'Ercole.
Correspondence should be addressed to G. K. Matsushima, University
of North Carolina Neuroscience Center, CB #7250, University of North
Carolina at Chapel Hill, Chapel Hill, NC 27599. E-mail: gkmats{at}med.unc.edu.
J. L. Mason's present address: Columbia University, 630 West
168th Street, Department of Pathology, New York, NY 10032.
D. D. Chaplin's present address: University of Alabama, 845 19th
Street South, Department of Microbiology, Birmingham, AL 35294.
| |
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ABSTRACT
INTRODUCTION
