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Regular Articles |
From the Departments of Neurosciences*
and Cell
Biology,
the Lerner Research Institute, the
Cleveland Clinic Foundation, Cleveland, Ohio; the Department of
Neurology,||
the Mellen Center for Multiple Sclerosis
Treatment and Research, The Cleveland Clinic Foundation, Cleveland,
Ohio; the Department of Neurology,
University
of Copenhagen, Glostrup Hospital, Glostrup, Denmark; Berlex
Biosciences,
Richmond, California; and the
Brain Research Institute,¶
University of Vienna,
Vienna, Austria
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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/CCL3. We analyzed expression of CCR1 and CCR5, the
monocyte receptors for these chemokines, on circulating and
cerebrospinal fluid CD14+ cells, and in MS brain lesions.
Approximately 70% of cerebrospinal fluid monocytes were
CCR1+/CCR5+, regardless of the presence of CNS
pathology, compared to less than 20% of circulating monocytes.
In active MS lesions CCR1+/CCR5+ monocytes were found in perivascular
cell cuffs and at the demyelinating edges of evolving lesions.
Mononuclear phagocytes in early demyelinating stages comprised
CCR1+/CCR5+ hematogenous monocytes and CCR1-/CCR5- resident
microglial cells. In later stages, phagocytic macrophages were
uniformly CCR1-/CCR5+. Cultured in vitro,
adherent monocytes/macrophages up-regulated CCR5 and down-regulated
CCR1 expression, compared to freshly-isolated monocytes. Taken
together, these findings suggest that monocytes competent to
enter the CNS compartment derive from a minority CCR1+/CCR5+ population
in the circulating pool. In the presence of ligand, these cells
will be retained in the CNS. During further activation in
lesions, infiltrating monocytes down-regulate CCR1 but not
CCR5, whereas microglia up-regulate CCR5.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The possible role of CC chemokine receptor 1 (CCR1), CCR5, and their
ligands in the pathogenesis of MS was first suggested by observations
in experimental autoimmune encephalomyelitis (EAE), an animal model for
MS. Inhibition/blockade of macrophage inflammatory protein (MIP)-1
(CCL3), a ligand for CCR1 and CCR5, prevented the development of both
acute and relapsing paralytic symptoms and infiltration of mononuclear
cells into the CNS. Importantly, anti-MIP-1 did not affect the
activation of encephalitogenic T cells, suggesting specificity of
MIP-1 for chemoattraction of mononuclear inflammatory cells into the
CNS in EAE mice.9-11
Mice lacking CCR1 (CCR1-/-)
developed significantly reduced incidence and severity of EAE when
compared with wild-type littermates. CCR1-/- spinal cords exhibited
less dense cellular infiltrates than cords from symptomatic wild-type
mice.12,13
In contrast, CCR5 seems dispensable for the development of EAE, because
CCR5-deficient mice are susceptible to EAE. Further, individuals
homozygous for a nonfunctional 
32 CCR5 develop MS.14
CCR5 may, however, have a role in determining MS severity, as
distinguished from MS susceptibility: genetic studies showed that
individuals heterozygous for the 32 nonfunctional CCR5 allele
experienced prolonged disease-free intervals, compared to individuals
with a fully functional CCR5 receptor.15,16
Consequently,
both CCR1 and CCR5 may be implicated in MS pathogenesis, but the
relationship between each receptor and disease susceptibility and/or
severity may be complex.
The hematogenous inflammatory component in MS can be examined and characterized in tissue sections as perivascular and parenchymal inflammatory cells. CNS-infiltrating leukocytes can also be identified in the lumbar cerebrospinal fluid (CSF). Therefore, we approached our investigation of CCR1 and CCR5 in MS in two ways: CCR1 and CCR5 expression on circulating and CSF CD14+ monocytes was examined by flow cytometry. Quantitative immunohistochemistry was applied to characterize chemokine receptor-positive cells in MS tissue sections during lesion evolution.
The results of these studies implicated CCR1+/CCR5+ cells as infiltrating and activated mononuclear phagocytes in MS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Flow cytometry studies evaluating CCR1 and CCR5 expression on
circulating and CSF monocytes, or co-expression of CCR1 with CCR5, were
performed in 24 patients with monosymptomatic optic neuritis and 26
patients with MS. In addition, 24 patients with other noninflammatory
neurological diseases who underwent diagnostic lumbar puncture were
included as controls. Optic neuritis patients had no history of
neurological symptoms and were diagnosed using established clinical
criteria.17
MS diagnosis was based on published criteria
for clinical research.18
The patients underwent lumbar
puncture and phlebotomy at the Glostrup Hospital, Glostrup, Denmark, or
the Department of Neurology, Cleveland Clinic Foundation, Cleveland,
Ohio. Patient characteristics are summarized in Table 1
. The Scientific Ethics Committee of the
Government of Denmark approved this study and informed consent was
obtained from all participants.
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CSF was collected directly on ice; centrifuged within 10 minutes after lumbar puncture at 250 x g for 10 minutes at 4°C, washed once in phosphate-buffered saline (PBS) with 1% human serum albumin and 0.1% sodium azide [fluorescence-activated cell sorting (FACS buffer)], and resuspended in ice cold FACS buffer. Phlebotomy was performed simultaneously with lumbar puncture; peripheral blood mononuclear cells were obtained by density gradient centrifugation on Lymphoprep (Nycomed, Oslo, Norway), washed three times at 4°C in PBS with 1% human serum albumin and resuspended in ice-cold FACS buffer. One hundred µl of CSF cells (minimum 4000 mononuclear cells) or 100 µl of peripheral blood mononuclear cells (100,000 mononuclear cells) were incubated on ice with antibodies for 30 minutes, washed twice in FACS buffer, and fixed with 1% paraformaldehyde. Analysis was performed on a FACSCalibur (Glostrup Hospital) or FACScan (Cleveland Clinic Foundation) flow cytometer (BD Biosciences, San Jose, CA), using CellQuest software (BD Biosciences). Cells were gated according to forward- and side-light-scattering properties and positively or negatively selected for CD14 or CD3 expression, respectively.
The following antibodies were used: phycoerythrin-conjugated anti-CCR1 (clone 53504.111; R&D Systems, Minneapolis, MN), fluorescein isothiocyanate- and phycoerythrin-conjugated anti-CCR5 (clone 2D7; BD PharMingen, San Diego, CA), allophycocyanin and peridinin chlorophyll protein-conjugated anti-CD14 (clone MøP9, BD Biosciences), fluorescein isothiocyanate-conjugated anti-CD3 (clone SK7, BD Biosciences) and phycoerythrin and fluorescein isothiocyanate-conjugated mouse isotype controls (BD Biosciences).
MS Autopsy Material
We focused these studies on active MS lesions, because cellular infiltration is proposed to be an initiating event in acute lesions. These studies, therefore, afforded an opportunity to examine the fate of CCR1+/CCR5+ monocytes that had newly entered the CNS. Paraffin-embedded archival autopsy material of five MS patients was available. The material was collected and neuropathologically examined at the Brain Research Institute, University of Vienna, Vienna, Austria. All five cases showed a prominent deposition of immunoglobulins and complement C9neo antigen at sites of active myelin destruction. Together with abundant T-cell and macrophage infiltrates and active demyelination, this form of tissue injury has been designated pattern II.2
In a total of 10 tissue sections 23 active lesions were identified and according to previously published criteria19-21 the following stages of demyelinating activity were defined: early-active (EA) regions were located at borders between demyelinating plaques and periplaque white matter. Macrophages contained myelin-degradation products, which stained with luxol fast blue myelin stain and were immunoreactive for all myelin proteins including minor proteins such as myelin oligodendrocyte glycoprotein. In late-active (LA) areas, myelin degradation was more advanced with macrophages containing myelin degradation products immunoreactive for the major myelin products myelin basic protein and proteolipid protein, but not for myelin oligodendrocyte glycoprotein. Inactive (IA) areas showed complete demyelination. Macrophages contained either empty vacuoles or periodic acid-Schiff reaction-positive degradation products.
In 11 of 23 lesions, all three stages of demyelinating activity could
be identified. Four lesions contained EA and LA areas. Six lesions were
entirely EA and two lesions IA. Ten representative regions outside
lesions, showing neither macroscopic nor histological evidence of
demyelination, were identified as internal controls (periplaque white
matter) (Table 2)
.
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Immunocytochemical analysis was performed using an avidin-biotin-horseradish peroxidase complex procedure and 3,3-diaminobenzidine as described previously.22 Berlex Biosciences provided a rabbit polyclonal anti-CCR1 antibody.23 Murine monoclonal anti-human CCR5 (clone 45549.111, mouse IgG2B) was obtained from R&D Systems, murine monoclonal anti-human MRP14 from Bachem Bioscience Inc., King of Prussia, PA (clone S 36.48, mouse IgG1), and murine monoclonal anti-CD68 (clone KP1, mouse IgG1) from DAKO Corporation, Carpinteria, CA. Primary antibodies were omitted in controls.
For analysis of co-localizations of CCR1 with CCR5, CCR1 with MRP14, and CCR5 with CD68 sections were simultaneously labeled with primary antibodies and then incubated with Texas Red- and fluorescein isothiocyanate-conjugated secondary antibodies (Southern Biotechnology Associates, Inc., Birmingham, AL). In controls, primary antibodies were omitted, and tests for cross-reactivity by secondary antibodies were performed. Sections were analyzed on a Leica TCS-NT confocal scanning laser microscope or a Leica DMR microscope (Leica Wetzlar, Heidelberg, Germany).
Morphometric Analysis
The number of immunostained cells was determined in at least four standardized fields (146,200 µm2, defined by a morphometric grid) from each of the distinct lesional areas. Sections were photographed on a Leica DMR microscope and an Optronix Magnafire digital camera system and analyzed using Image Pro Plus (Media Cybernetics, Silver spring, MD).
Isolation and Culture of Human Monocytes
To examine CCR1 and CCR5 expression during monocyte differentiation in vitro, monocytes were obtained from freshly donated human peripheral blood from five healthy donors (three females and two males; mean age, 33 years; range, 21 to 43 years). The blood was immediately diluted 1:1 with PBS containing 1% human albumin (Sigma, St. Louis, MO) and underlayered with Ficoll-Paque (Pharmacia, Piscataway, NJ) for separation of mononuclear cells by density centrifugation. Monocytes were separated by adherence to serum-coated flasks according to the method of Kumagai and colleagues24 and subsequently detached using 0.5 mmol/L of ethylenediaminetetraacetic acid. This preparation contained >95% monocytes as determined by flow cytometry for CD14 surface expression. Isolated monocytes were cultured in Dulbecco’s modified Eagle Medium (Mediatech Cellgro Inc., Herndon, VA) supplemented with L-glutamine, 4.5 mg/L glucose, and 10% bovine calf serum (Hyclone, Logan, UT) for 7 days at 37°C and 10% CO2. Under these conditions monocytes differentiate into macrophages after 7 days.25,26 Granulocyte macrophage-colony-stimulating factor was omitted in the cell culture medium because this might alter chemokine surface expression levels.26 After 1 day or 7 days in culture cells were detached from the flask using 0.5 mmol/L of ethylenediaminetetraacetic acid and gentle scraping and resuspended in PBS. CCR1 and CCR5 expression was determined by flow cytometry.
Statistical Analysis
Nonparametric tests (Mann-Whitney test and Wilcoxon signed rank test) were applied because the data were not normally distributed (Kolmogorovv-Smirnov test). A P value <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CCR1 and CCR5 expression on CD14+ monocytes in peripheral blood
and CSF was compared in patients with optic neuritis, MS, and
neurological controls. Approximately 90% of CSF monocytes expressed
CCR1 and 
80% expressed CCR5, which was significantly
(P < 0.001) higher compared to peripheral
blood. There were no differences between the three patient groups
examined (Figure 1)
.
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Together, these results indicate that CCR1+/CCR5+ monocytes, although a minority of the circulating monocyte pool, are highly enriched in the CSF population, regardless of the presence of CNS inflammatory pathology.
Distribution of Mononuclear Phagocytes in Acute MS Lesions
To follow the fate of CCR1+/CCR5+ hematogenous monocytes in MS lesions, immunohistochemistry for CD68, CCR5, and CCR1 was performed on 10 tissue sections of five patients with MS and distribution of immunoreactive cells in relation to demyelinating activity was established. In the 10 available tissue sections 23 lesions were identified containing 21 areas of EA demyelination, 15 LA regions, and 13 IA areas.
In EA zones two populations of CD68+ cells were observed: perivascular
CD68+ cells had the appearance of activated monocytes with prominent
granular cytoplasm, whereas parenchymal CD68+ cells exhibited
predominantly the morphology of activated process-bearing microglia
(Figure 2A)
.
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. Perivascular CCR5+ cells were comprised both of CD68+
monocytes and CD3+ lymphocytes. Dual-label immunofluorescence
histochemistry and confocal microscopy for CD68 and CCR5 localized
CD68+/CCR5+ double-positive cells to perivascular accumulations of EA
regions, with CD68-single-positive microglial cells detected in the
parenchyma (Figure 2C)
.
In contrast to EA zones, CD68+ cells in LA areas comprised a
homogenous population of large, strongly CD68-immunoreactive phagocytic
macrophages (Figure 2D)
.
CCR5+ cells in LA regions resembled large phagocytic cells and
were predominantly found in the parenchyma (Figure 2E)
. In serial
section analysis and dual-label immunohistochemistry, CD68+ phagocytic
parenchymal macrophages in LA regions uniformly expressed CCR5
(Figure 2F)
.
CD68 and CCR5 immunoreactivity in IA zones was essentially identical with that observed in LA regions (data not shown).
CCR1+ cells were predominantly localized at lesion edges and within
areas of EA demyelination (Figure 3
; A,
B, D, and F). In serial section analyses CCR1+ cells co-localized with
CD68+ cells, but not with CD3 immunoreactivity (data not shown). CCR1+
cells in EA areas were either perivascular or in parenchymal foci of
active demyelination (Figure 3B)
. Both perivascular and parenchymal
CCR1+ cells exhibited the morphology of monocytes (Figure 3D)
. Dual-label immunofluorescence histochemistry and confocal
microscopy localized CCR1+/CCR5+ cells predominantly to perivascular
cell aggregates in EA regions (Figure 3E)
. As in CSF, all CCR1+ cells
were CCR5+, whereas CCR5+ cells were not invariably CCR1+. CCR1+ cells
at lesion edges were small, round cells (Figure 3F)
that co-localized
with macrophage-related protein (MRP)14+ cells (Figure 3, C and G)
.
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In summary, in EA zones mononuclear phagocytes formed a heterogeneous population of CCR1+/CCR5+ perivascular monocytes and parenchymal CCR1-/CCR5- microglial cells. In LA and IA zones a homogenous population of monocyte- and microglia-derived mononuclear phagocytes were CCR1-/CCR5+.
Quantification of Mononuclear Phagocytes in Relation to Demyelinating Activity
The density of CD68+ cells was significantly
(P < 0.001) higher in EA, LA, and IA zones,
compared to periplaque white matter, with consistent CD68 counts within
the different zones of individual lesions (Table 3
and Figure 4A
), indicating that the transition from
EA to LA and IA demyelination in these lesions was characterized by
monocyte and microglia activation and redistribution, rather than
continuous accumulation of newly infiltrating cells from the
bloodstream.
|
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. This
density was significantly (P < 0.001), 100-fold
higher than in periplaque white matter (4.9 ± 2.2
cells/mm2) and represented a mean of 25% (5 to
54%) of CD68+ cells in EA areas. In LA areas, 271 ± 54.3
cells/mm2
(16%, 3 to 44% of CD68+ cells)
expressed CCR1. Compared to EA and LA, IA areas had a significant (EA
versus IA P < 0.001, LA versus
IA P < 0.05) lower density of CCR1+ cells (128.9
± 25.1 cells/mm2; 7%, 1 to 27%).
Quantitative immunohistochemical analysis of CCR5 expression in EA
areas revealed 705 ± 64 cells/mm2
(mean ± SEM, Figure 4C
). This number represented significantly
(P < 0.05) more CCR5+ cells than found in
periplaque white matter (65 ± 25
cells/mm2), and constituted a mean of 42%
(range, 13 to 67%) of CD68+ cells within EA areas. The density of
CCR5+ cells was significantly (P < 0.001)
higher in areas of LA demyelination, compared with EA regions. In LA
areas, a mean of 1599 ± 145 cells/mm2
expressed CCR5. In these regions, CCR5+ cells represented 94% (62 to
205%) of CD68+ cells. In IA areas, CCR5 expression was 1480 ±
181 cells/mm2, representing 84% (18 to 152%) of
CD68+ cells.
Expression of CCR1 and CCR5 Was Differentially Regulated during Monocyte Differentiation in Vitro
To investigate regulation of CCR1 and CCR5 expression during
monocyte maturation in vitro, chemokine receptor expression
on freshly isolated monocytes and at two different time points during
monocyte differentiation in culture was examined by flow cytometry.
Thirty-four percent (27.9 to 41%) of freshly-isolated monocytes
expressed CCR1, whereas 9.7% (4.5 to 17.6%) expressed CCR5 (Figure 5
, top). After 7 days in culture the
cells had become enlarged or spindle-shaped with extended processes
(Figure 5
; A to C, bottom). After 1 and 7 days in culture CCR1 was
expressed by 4.7% (2.1 to 6.7%, P < 0.01) and 2.5%
(1.5 to 3.4%), respectively.
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These in vitro results indicate that mature macrophages express very low levels of CCR1 and high levels of CCR5 expression, compared to freshly isolated monocytes.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/CCL3, in the pathogenesis of inflammatory
demyelination. Both chemokine receptors were highly enriched on
monocytes in the CSF compartment and in perivascular cell accumulations
in acute MS lesions. Furthermore, differential expression patterns for
CCR1 and CCR5 were observed during lesion evolution and during culture
of human monocytes in vitro. These results provide insight
into pathogenetic mechanisms during early demyelinating events in MS
and identify targets for future study and potential therapeutic
intervention. Hematogenous Monocytes that Enter the CNS Are CCR1+/CCR5+
In this report, we provide evidence that hematogenous monocytes
that infiltrate the CNS are CCR1+/CCR5+. This evidence is primarily
based on findings of our flow cytometry studies showing that a majority
of monocytes in the CSF compartment were CCR1+/CCR5+ (Figure 1)
. This
CCR1+/CCR5+ population constituted a minority of the
circulating pool of monocytes. Consistent with the hypothesis that the
lumbar CSF is in equilibrium with the perivascular space of the CNS
white matter, dual-label immunohistochemistry revealed CCR1+/CCR5+
perivascular cell accumulations in early demyelinating regions (Figure 3E)
.
Although enrichment of CCR1+/CCR5+ monocytes in the CSF compartment was observed independent of CNS pathology, CCR1+/CCR5+ perivascular cell accumulations have not been detected in noninflamed brain sections (unpublished observations). We therefore propose that CCR1+/CCR5+ monocytes will only be retained in the CNS perivascular space in the presence of appropriate ligands, such as RANTES, which is present in CSF of MS patients and is abundantly expressed by the perivascular elements of MS lesions.22
CCR1+ cells at MS lesion edges co-expressed the macrophage-related
protein (MRP) 14 (Figure 3G)
, a 14-kd calcium-binding protein expressed
primarily by circulating human neutrophils and
monocytes.27
In vitro, this antigen
shows a decline in expression during monocyte
differentiation.28
In MS lesions, MRP-14 expression is
associated with the earliest stage of macrophage-mediated demyelinating
activity.19
It is uncertain whether MRP14 can be expressed
by microglia under certain pathological conditions. In MS lesions, we
and others detected MRP-14 expression only on small round,
nonprocess-bearing cells, morphologically consistent with monocytes
(Figure 3C)
.19
Co-expression of CCR1 and MRP-14 was
therefore interpreted as identifying a population of newly recruited
hematogenous monocytes.
Hematogenous Monocytes and Resident Microglia Show Different Chemokine Receptor Expression Patterns during Early Demyelination
In EA zones, a mean of 25% of CD68+ mononuclear phagocytes
expressed CCR1 whereas a mean of 42% of CD68+ cells expressed CCR5. If
the majority of hematogenous monocytes in the CNS are CCR1+/CCR5+, the
remaining 58 to 75% of CCR1-/CCR5-/CD68+ mononuclear phagocytes most
plausibly represent resident microglial cells. This interpretation was
also supported by the distribution and morphology of CD68+ cells in EA
areas, where we identified two distinct populations. One CD68+
population was identical to CCR1+/CCR5+ perivascular monocytes. The
second population of CD68+ cells exhibited the morphology of
parenchymal microglia (Figure 2A)
. CD68+ cells with microglial
morphology did not co-localize with CCR1 or CCR5 immunoreactivity and
were concentrated in and around regions of EA demyelination (Figure 2C)
. Based on these data, we propose that initial effectors of
demyelination in MS lesions include CCR1+/CCR5+ hematogenous monocytes
as well as CCR1-/CCR5- resident parenchymal microglial cells.
Lesion Evolution Is Characterized by Activation, rather than Accumulation of Monocytes from the Blood Stream
We and others found that numbers of CD68+ cells in EA, LA, and IA
regions of individual active MS lesions remained virtually unchanged
(Figure 4A
and Table 3
).19,29
These observations led to
the interpretation that changes in the CD68+ population occurred via
activation and redistribution in the absence of meaningful continuous
invasion of cells from the bloodstream. Another possibility is that
large numbers of CD68+ cells undergo apoptosis in EA regions of MS
lesions and are quantitatively replaced by hematogenous cells. Arguing
against this interpretation, analyses of apoptotic cells in MS lesions
have not reported dying macrophages or microglial cells in numbers
sufficient to offer an alternative explanation of our
results.30,31
Expression of CCR1 and CCR5 Are Differentially Regulated during Lesion Evolution
The number of CCR5+ cells was significantly higher in LA and IA
regions compared to EA regions (Figure 4C)
, suggesting that CCR5
expression is not only maintained by the infiltrating hematogenous
monocyte population throughout time but was also up-regulated by
resident, initially CCR5-negative, microglial cells during activation
and transformation into mature macrophages. In contrast, we observed a
significant lower number of CCR1-expressing monocytes in IA regions
compared to EA and LA areas (Figure 4B)
. How can differential
regulation of CCR1 and CCR5 expression during MS lesion evolution be
explained? Expression of chemokine receptors on the cell surface is a
result of a complex interplay of regulatory mechanisms including
cytokine stimulation, ligand-induced internalization, as well as
differentiation and activation of the receptor-bearing cell. Here, we
report that the expression of CCR1 and CCR5 on human monocytes is
differentially regulated during monocyte maturation in vitro
(Figure 5)
. As reported previously, we found higher CCR5 surface
expression on macrophages when compared to freshly isolated
monocytes.26,32
Our data constitute the first report that
CCR1 surface expression is down-regulated during monocyte
differentiation in vitro. The loss of CCR1 and the gain of
CCR5 expression during MS lesion evolution might therefore be explained
by an increased activation and maturation of the infiltrating
hematogenous monocyte population.
In considering the implications of our findings for MS pathogenesis, it is pertinent that chemokine receptors mediate effects beyond chemotaxis, some of which could be important for MS pathogenesis.33 These effects include direct induction of IL-1234 and nitric oxide production as well as modulation of cytokine release.35-37
Our results provide insight into potential mechanisms of trafficking and activation of hematogenous monocytes in the CNS of MS patients. The challenge for the future is to define the roles of these components in disease pathogenesis.
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Acknowledgements |
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Footnotes |
|---|
Supported by the National Institutes of Health (1PO1 NS38667 to R. M. R.), the Williams Fund for MS Research (to R. M. R.), the Deutsche Forschungsgemeinschaft, Germany (TR463/1-1 to C. T.), the P. Carl Petersen Foundation, Denmark (to T. L. S.), the Niels Ydes Foundation, Denmark (to T. L. S.), and Bundesministerium für Bildung, Wissenschaft und Kultur, Austria (GZ 70.056/2-Pr/4/99 to H. L.).
C. T. and T. L. S. contributed equally to this work.
Accepted for publication July 23, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+ dendritic cells. Nat Immunol 2000, 1:83-87[Medline]
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