Piet Mondrian's trees and the evolution in understanding multiple sclerosis, Charcot Prize Lecture 2011
MULTIPLE SCLEROSIS JOURNAL
2013; 19 (1): 5-14
Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
2012; 16 (8): 1866-1877
Four questions were posed about multiple sclerosis (MS) at the 2011 Charcot Lecture, Oct. 22, 2011. 1. The Male/Female Disparity: Why are women developing MS so much more frequently than men? 2. Neuronal and Glial Protection: Are there guardian molecules that protect the nervous system in MS? 3. Predictive Medicine: With all the approved drugs, how can we rationally decide which one to use? 4. The Precise Scalpel vs. the Big Hammer for Therapy: Is antigen-specific therapy for demyelinating disease possible? To emphasize how our views on the pathogenesis and treatment of MS are evolving, and given the location of the talk in Amsterdam, Piet Mondrian's progressive interpretations of trees serve as a heuristic.
View details for DOI 10.1177/1352458512470730
View details for Web of Science ID 000313272100003
View details for PubMedID 23303879
Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of beta-Amyloid in T(H)1 and T(H)17 Versions of Experimental Autoimmune Encephalomyelitis
SCIENCE TRANSLATIONAL MEDICINE
2012; 4 (145)
Previously, we have shown that CCR5 transcription is regulated by CREB-1. However, the ubiquitous pattern of CREB-1 expression suggests the involvement of an additional level of transcriptional control in the cell type-specific expression of CCR5. In this study, we show that epigenetic changes (i.e. DNA methylation and histone modifications) within the context of the CCR5 P1 promoter region correlate with transcript levels of CCR5 in healthy and in malignant CD4(+) T lymphocytes as well as in CD14(+) monocytes. In normal naïve T cells and CD14(+) monocytes the CCR5 P1 promoter resembles a bivalent chromatin state, with both repressive and permissive histone methylation and acetylation marks. The CCR5-expressing CD14(+) monocytes however show much higher levels of acetylated histone H3 (AcH3) compared to the non-CCR5-expressing naïve T cells. Combined with a highly methylated promoter in CD14(+) monocytes, this indicates a dominant role for AcH3 in CCR5 transcription. We also show that pharmacological interference in the epigenetic repressive mechanisms that account for the lack of CCR5 transcription in T leukaemic cell lines results in an increase in CREB-1 association with CCR5 P1 chromatin. Furthermore, RNA polymerase II was also recruited into CCR5 P1 chromatin resulting in CCR5 re-expression. Together, these data indicate that epigenetic modifications of DNA, and of histones, contribute to the control of CCR5 transcription in immune effector cells.
View details for DOI 10.1111/j.1582-4934.2011.01482.x
View details for Web of Science ID 000306909200023
View details for PubMedID 22050776
Statins amplify TLR-induced responses in microglia via inhibition of cholesterol biosynthesis
2012; 60 (1): 43-52
?-Amyloid 42 (A?42) and ?-amyloid 40 (A?40), major components of senile plaque deposits in Alzheimer's disease, are considered neurotoxic and proinflammatory. In multiple sclerosis, A?42 is up-regulated in brain lesions and damaged axons. We found, unexpectedly, that treatment with either A?42 or A?40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. A?42 and A?40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive T helper 1 (T(H)1) or T(H)17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo A?42 and A?40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major proinflammatory cytokines and chemokines were reduced in the blood after A? peptide treatment. Protection conferred by A? treatment did not require its delivery to the brain: Adoptive transfer with lymphocytes from donors treated with A?42 attenuated EAE in wild-type recipient mice, and A? deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with A? treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of A?, there is exacerbated clinical EAE disease progression. Because A?42 and A?40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.
View details for DOI 10.1126/scitranslmed.3004145
View details for Web of Science ID 000307159500004
View details for PubMedID 22855462
Common variants in P2RY11 are associated with narcolepsy
2011; 43 (1): 66-U90
Statins inhibit the endogenous intracellular mevalonate pathway and exposure to statins affects innate and adaptive immune responses. Different statins are currently under evaluation as (co)therapy in neuro-inflammatory diseases like multiple sclerosis. However, there are important discrepancies in the reported effects of statins on innate immune responses in different cell types. Studies to characterize such responses in clinically relevant primary cells are currently lacking. In this study, we investigated the effect of statins on Toll-like receptor (TLR)-induced responses of microglia, the resident macrophages of the central nervous system (CNS). Exposure of primary microglia from adult rhesus monkeys to different statins strongly amplified pro-inflammatory cytokine protein and mRNA levels in response to myeloid differentiation primary response gene 88-dependent TLR activation in particular. Rather than affecting nuclear facor-?B activation levels, statin exposure affected stress-activated protein/Jun-amino-terminal and p38 kinase signaling pathways. Mechanistic studies using specific pathway inhibitors and rescue experiments show that statin-induced inhibition of cholesterol biosynthesis, rather than inhibition of isoprenylation, was mainly responsible for the amplified TLR responses. Additionally, microglia were more sensitive to statin-mediated effects than bone marrow-derived macrophages of the same donor. This correlated to lower intrinsic microglial expression levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the enzyme targeted by statins. Amplification of TLR-induced responses in microglia by statin exposure might contribute to the generation of a more pro-inflammatory CNS microenvironment which can be of relevance for the pathogenesis of neuroinflammatory disorders.
View details for DOI 10.1002/glia.21245
View details for Web of Science ID 000297213400004
View details for PubMedID 21964955
CC chemokine receptor 5 gene promoter activation by the cyclic AMP response element binding transcription factor
2008; 112 (5): 1610-1619
Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y?? gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10?¹?, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.
View details for DOI 10.1038/ng.734
View details for Web of Science ID 000285683500018
View details for PubMedID 21170044
Immunomodulation by statins: Inhibition of cholesterol vs. isoprenoid biosynthesis
BIOMEDICINE & PHARMACOTHERAPY
2007; 61 (7): 400-407
The chemokine receptor CCR5 is implicated in the pathogenesis of various inflammatory diseases, such as multiple sclerosis (MS), atherosclerosis, transplant rejection, and autoimmunity. In previous studies, we have shown that MS lesions are characterized by enhanced expression of transcription factors associated with stress responses, ie, IRF-1, NF-kappaB, and CREB-1, which modulate expression of both classes of major histocompatibility complex (MHC) molecules. The expression of MHC-I and MHC-II molecules greatly overlaps with the expression of CCR5 in MS lesions. Therefore, we investigated whether these factors are also involved in the transcriptional regulation of CCR5. Using in vitro assays, we determined that neither IRF-1 nor NF-kappaB is involved in the activation of the CCR5 promoter. This is corroborated by the finding that these factors are not involved in the induction of endogenous CCR5 transcription in various cell types. In contrast, we show that CCR5 expression is regulated by the cAMP/CREB pathway and that interference in this pathway affects endogenous CCR5 transcription. From this, we conclude that the cAMP/CREB pathway is involved in the regulation of CCR5 transcription and that, given the ubiquitous nature of CREB-1 protein expression, additional regulatory mechanisms must contribute to cell type-specific expression of CCR5.
View details for DOI 10.1182/blood-2008-01-135111
View details for Web of Science ID 000258956200014
View details for PubMedID 18511806
Simvastatin affects cell motility and actin cytoskeleton distribution of microglia
2006; 53 (2): 115-123
Due to their ability to inhibit the synthesis of cholesterol, statins are widely used in medical practice and are the principal therapy for hypercholesterolemia. In addition, various findings suggest that statins also exert anti-inflammatory properties and may so play a role in modulating the immune system. Because of these properties, statins could provide a potential treatment for various chronic inflammatory diseases, including neuroinflammatory disorders such as multiple sclerosis. Here, we will review the effect of statins on the expression and function of a variety of immune relevant molecules and the underlying mechanisms that contribute to the immunomodulatory properties of statins. In this discussion we will also evaluate the effects of statins on central nervous system cells to emphasize the potential of these agents in the treatment of neuroinflammatory disorders.
View details for DOI 10.1016/j.biopha.2007.06.005
View details for Web of Science ID 000249323900004
View details for PubMedID 17643927
Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing Microdomains
2005; 66 (6): 653-665
Statin treatment is proposed to be a new potential therapy for multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. The effects of statin treatment on brain cells, however, are hardly understood. We therefore evaluated the effects of simvastatin treatment on the migratory capacity of brain microglial cells, key elements in the pathogenesis of MS. It is shown that exposure of human and murine microglial cells to simvastatin reduced cell surface expression of the chemokine receptors CCR5 and CXCR3. In addition, simvastatin treatment specifically abolished chemokine-induced microglial cell motility, altered actin cytoskeleton distribution, and led to changes in intracellular vesicles. These data clearly show that simvastatin inhibits several immunological properties of microglia, which may provide a rationale for statin treatment in MS.
View details for DOI 10.1002/glia.20269
View details for Web of Science ID 000233847100001
View details for PubMedID 16206159
Statins and control of MHC2TA gene transcription
2005; 11 (4): 365-366
Transcriptional regulation of antigen presentation
CURRENT OPINION IN IMMUNOLOGY
2004; 16 (1): 67-75
Statins, the main therapy for hypercholesterolemia, are currently considered as possible immunomodulatory agents. Statins inhibit the production of proinflammatory cytokines and reduce the expression of several immunoregulatory molecules, including major histocompatibility complex class II (MHC-II) molecules. In this study, we investigated the mechanism by which simvastatin reduces the membrane expression of MHC-II molecules on several human cell types. We demonstrate that the reduction of MHC-II membrane expression by simvastatin correlates with disruption of cholesterol-containing microdomains, which transport and concentrate MHC-II molecules to the cell surface. In addition, we demonstrate that statins reduce cell-surface expression of other immunoregulatory molecules, which include MHC-I, CD3, CD4, CD8, CD28, CD40, CD80, CD86, and CD54. Our observations indicate that the downregulation of MHC-II at the cell surface contributes to the immunomodulatory properties of statins and is achieved through disruption of cholesterol-containing microdomains, which are involved in their intracellular transport.
View details for DOI 10.1016/j.humimm.2005.04.004
View details for Web of Science ID 000230868800003
View details for PubMedID 15993711
CX(3)CL1 and CX(3)CR1 expression in human brain tissue: Noninflammatory control versus multiple sclerosis
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
2003; 62 (9): 899-907
MHC class I and class II molecules play essential roles in the adaptive immune response by virtue of their ability to present peptides to T lymphocytes. Given their central role in adaptive immunity, the genes encoding these peptide-presenting molecules are regulated in a tight fashion to meet with local requirements for an adequate immune response. In contrast to MHC class I gene products, which are expressed on almost all nucleated cells, constitutive expression of MHC class II molecules is found only in specialized antigen-presenting cells of the immune system. Expression of both classes of MHC molecules can be induced by immune regulators and upon cell activation. A set of conserved cis-acting regulatory promoter elements mediate the transcription of MHC class I and beta2-microglobulin genes. Of these regulatory elements, the promoters of MHC class II and accessory genes also have the SXY module. The MHC class II transactivator (CIITA) is essential for the activation of MHC class II promoters, and it functions through protein-protein interactions with regulatory factors bound to the SXY module. Given the central role of CIITA in these regulatory processes, it is of interest to identify the DNA-binding factors and co-activators that assemble on CIITA promoters in a cell-type-specific fashion. Accordingly, recent studies include investigations into chromatin remodeling and epigenetic control mechanisms that modulate cell-type-specific transcriptional regulation of genes involved in antigen presentation.
View details for DOI 10.1016/j.coi.2003.11.015
View details for Web of Science ID 000188763500011
View details for PubMedID 14734112
An important role for CX3CL1 in neuroinflammation and neurodegeneration has been suggested in recent publications. In this study, we compared the expression of CX3CL1 and its receptor CX3CR1 in human brain tissue derived from control patients without neurological complications and in multiple sclerosis (MS) patients. Results from this study demonstrate that CX3CL1 is constitutively expressed in human central nervous system (CNS) astrocytes in vivo and under basal conditions in human adult astrocyte cultures. CX3CR1 is expressed on astrocytes and microglial cells both in vivo and in vitro. Chemotaxis assay shows a functional response upon CX3CR1 signaling in microglial cells. Although CX3CL1 expression is upregulated in cultured astrocytes in response to proinflammatory cytokines, no evidence for expression differences of CX3CL1 between control patients and MS patients was found. Our data suggest that CX3CL1 has more general physiological functions, which occur also in the absence of proinflammatory conditions.
View details for Web of Science ID 000185460400002
View details for PubMedID 14533779