Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated, autoimmune disease of the central nervous system (CNS) that serves as a model for various cellular and molecular aspects of the human disease, multiple sclerosis (MS). Although EAE has long been considered a T cell-mediated disease, macrophages play a role in disease pathogenesis and are known to accumulate in the CNS under the control of chemokines. In the present report we demonstrate that mice induced to develop EAE were treated with a small molecular weight molecule that suppresses proinflammatory cytokine production which resulted in significantly decreased clinical EAE, CNS CCL2 expression and CNS macrophage accumulation. These results demonstrate the efficacy of a novel class of therapeutic molecules for CNS demyelinating disease.
 ...
PMID:Inhibition of experimental autoimmune encephalomyelitis by a novel small molecular weight proinflammatory cytokine suppressing drug. 1867 15

Massive T cell infiltration into the central nervous system is a hallmark of multiple sclerosis (MS) and its rodent model experimental autoimmune encephalomyelitis (EAE), resulting in the induction of many of the pathophysiological events that lead to neuroinflammation and neurodegeneration. Thus, blocking T cell migration into the central nervous system may reduce disease severity in MS and EAE. One potential target for reducing T cell migration is inhibition of the Ca(2+)-activated neutral protease calpain. Previous studies in other cell types have demonstrated that migration is reduced by incubation of cells with calpain inhibitors. Thus, we hypothesize that calpain inhibition will reduce migration of T cells in response to and toward the chemokine CCL2. To test this hypothesis, the intracellular free Ca(2+) levels in Jurkat E6-1 T cells was first measured by the fura-2 assay to assess whether the intracellular ion environment would support calpain activation. The intracellular free Ca(2+) levels were found to increase in response to CCL2. The cells were next treated with the calpain inhibitor calpeptin in a multiwelled Boyden chamber with CCL2 used as the chemoattractant. These studies demonstrate that inhibition of calpain with its inhibitor calpeptin produces a dose-dependent inhibition of chemotaxis. Calpain activity, as measured by live cell imaging, was also increased in response to CCL2, providing further evidence of its involvement in the process of chemotaxis and migration. These studies provide evidence for the involvement of calpain in the mechanisms of chemotaxis and warrants further exploration in MS patient and EAE animal samples.
 ...
PMID:Involvement of calpain in the process of Jurkat T cell chemotaxis. 1883 Oct 7

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a widely expressed neuropeptide originally discovered in the hypothalamus. It closely resembles vasoactive intestinal peptide (VIP), a neuropeptide well known to inhibit macrophage activity, promote Th2-type responses, and enhance regulatory T cell (Treg) production. Recent studies have shown that administration of PACAP, like VIP, can attenuate dramatically the clinical and pathological features of murine models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. However, specific roles (if any) of endogenous VIP and PACAP in the protection against autoimmune diseases have not been explored. Here, we subjected PACAP-deficient mice to myelin oligodendrocyte glycoprotein (MOG(35-55))-induced EAE. MOG immunization of PACAP-deficient mice triggered heightened clinical and pathological manifestations of EAE compared to wild-type mice. The increased sensitivity was accompanied by enhanced mRNA expression of proinflammatory cytokines (TNFalpha, IL-6, IFN-gamma, IL-12p35, IL-23p19, and IL-17), chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, and RANTES/CCL5), and chemotactic factor receptors (CCR1, CCR2, and CCR5), but downregulation of the anti-inflammatory cytokines (IL-4, IL-10, and TGF-beta) in the spinal cord. Moreover, the abundance of CD4(+)CD25(+)FoxP3(+) Tregs in lymph nodes and levels of FoxP3 mRNA in the spinal cord were also diminished. The reduction in Tregs was associated with increased proliferation and decreased TGF-beta secretion in lymph node cultures stimulated with MOG. These results demonstrate that endogenous PACAP provides protection in EAE and identify PACAP as an intrinsic regulator of Treg abundance after inflammation.
 ...
PMID:Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis. 1919 Jan 79

Theiler's murine encephalomyelitis virus (TMEV) infection directly induces many proinflammatory genes, including type I interferon (IFN) and a variety of cytokine genes. These virus-induced cytokines are a critical factor in developing TMEV-induced demyelinating disease. We have previously reported that the major activation signal for the cytokine genes is mediated via TLR3. In this study, we describe that TLR2 is upregulated via TLR3 signal and cooperatively participates in the expression of IL-6, IL-1beta, CCL2, and CCL5 genes following TMEV infection. The expression of these genes was significantly impaired in both TLR2-deficient and TLR3-deficient primary astrocytes. However, the induction of type I IFNs was not affected by TLR2 deficiency in the primary cells. TMEV infection led to TLR2-mediated NF-kappaB activation, but not IRF3 or IRF7 activation, critical for type I IFN production. More importantly, TLR3 was required for TMEV-induced early TLR2 upregulation in primary astrocytes leading to the production of TLR2-dependent cytokines such as IL-6. Interestingly, soluble factor(s) produced via TLR2/3-dependent signals appears to be partially associated with the downstream cytokine production. These results indicate that TMEV utilizes TLR3-induced TLR2 to induce inflammatory cytokines, which are critical to the development of immune-mediated demyelinating disease.
 ...
PMID:Theiler's virus infection induces TLR3-dependent upregulation of TLR2 critical for proinflammatory cytokine production. 1919 35

The administration of ex vivo culture-expanded mesenchymal stromal cells (MSCs) has been shown to reverse symptomatic neuroinflammation observed in experimental autoimmune encephalomyelitis (EAE). The mechanism by which this therapeutic effect occurs remains unknown. In an effort to decipher MSC mode of action, we found that MSC conditioned medium inhibits EAE-derived CD4 T cell activation by suppressing STAT3 phosphorylation via MSC-derived CCL2. Further analysis demonstrates that the effect is dependent on MSC-driven matrix metalloproteinase proteolytic processing of CCL2 to an antagonistic derivative. We also show that antagonistic CCL2 suppresses phosphorylation of AKT and leads to a reciprocal increased phosphorylation of ERK associated with an up-regulation of B7.H1 in CD4 T cells derived from EAE mice. CD4 T cell infiltration of the spinal cord of MSC-treated group was robustly decreased along with reduced plasma levels of IL-17 and TNF-alpha levels and in vitro from restimulated splenocytes. The key role of MSC-derived CCL2 was confirmed by the observed loss of function of CCL2(-/-) MSCs in EAE mice. In summary, this is the first report of MSCs modulating EAE biology via the paracrine conversion of CCL2 from agonist to antagonist of CD4 Th17 cell function.
 ...
PMID:Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. 1941 50

CCL2 is a key CC chemokine that has been implicated in a variety of inflammatory autoimmune diseases and in tumor progression and it is therefore an important target for therapeutic intervention in these diseases. Soluble receptor-based therapy is a known approach for neutralizing the in vivo functions of soluble mediators. Owing to the complexity of seven-transmembrane G protein-coupled receptors, efforts to generate neutralizing soluble chemokine receptors have so far failed. We developed a strategy that is based on the generation of short recombinant proteins encoding different segments of a G protein-coupled receptor, and tested the ability of each of them to bind and neutralize its target chemokine. We show that a fusion protein comprised of as few as 20 aa of the third extracellular (E3) domain of the CCL2 receptor, stabilized by the IgG H chain Fc domain (E3-IgG or BL-2030), selectively binds CCL2 and CCL16 and effectively neutralizes their biological activities. More importantly, E3-IgG (BL-2030) could effectively suppress the in vivo biological activity of CCL2, attenuating ongoing experimental autoimmune encephalomyelitis, as well as the development of human prostate tumor in SCID mice.
 ...
PMID:A novel recombinant fusion protein encoding a 20-amino acid residue of the third extracellular (E3) domain of CCR2 neutralizes the biological activity of CCL2. 1953 19

CCR2 chemokine receptor signaling has been implicated in the generation of diverse types of neuropathology, including neuropathic pain. For example, ccr2 knock-out mice are resistant to the establishment of neuropathic pain, and mice overexpressing its ligand, monocyte chemoattractant protein-1 (MCP1; also known as CCL2), show enhanced pain sensitivity. However, whether CCR2 receptor activation occurs in the central or peripheral nervous system in states of neuropathic pain has not been clear. We developed a novel method for visualizing CCR2 receptor activation in vivo by generating bitransgenic reporter mice in which the chemokine receptor CCR2 and its ligand MCP1 were labeled by the fluorescent proteins enhanced green fluorescent protein and monomeric red fluorescent protein-1, respectively. CCR2 receptor activation under conditions such as acute inflammation and experimental autoimmune encephalomyelitis could be faithfully visualized by using these mice. We examined the status of CCR2 receptor activation in a demyelination injury model of neuropathic pain and found that MCP1-induced CCR2 receptor activation mainly occurred in the peripheral nervous system, including the injured peripheral nerve and dorsal root ganglia. These data explain the rapid antinociceptive effects of peripherally administered CCR2 antagonists under these circumstances, suggesting that CCR2 antagonists may ameliorate pain by inhibiting CCR2 receptor activation in the periphery. The method developed here for visualizing CCR2 receptor activation in vivo may be extended to G-protein-coupled receptors (GPCRs) in general and will be valuable for studying intercellular GPCR-mediated communication in vivo.
 ...
PMID:Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain. 1955 45

Infection with mouse adenovirus type 1 (MAV-1) results in fatal acute encephalomyelitis in susceptible mouse strains via infection of brain endothelial cells. Wild-type (wt) MAV-1 causes less brain inflammation than an early region 3 (E3) null virus in C57BL/6 mice. A mouse brain microvascular endothelial cell line infected with wt MAV-1 had higher expression of mRNAs for the proinflammatory chemokines CCL2 and CCL5 than mock- and E3 null virus-infected cells. Primary mouse brain endothelial cells infected with wt virus had elevated levels of CCL2 compared to mock- or E3 null virus-infected cells. Infection of C57BL/6 mice with wt MAV-1 or the E3 null virus caused a dose-dependent breakdown of the blood-brain barrier, primarily due to direct effects of virus infection rather than inflammation. The tight junction proteins claudin-5 and occludin showed reduced surface expression on primary mouse brain endothelial cells following infection with either wt MAV-1 or the E3 null virus. mRNAs and protein for claudin-5, occludin, and zona occludens 2 were also reduced in infected cells. MAV-1 infection caused a loss of transendothelial electrical resistance in primary mouse brain endothelial cells that was not dependent on E3 or on MAV-1-induced CCL2 expression. Taken together, these results demonstrate that MAV-1 infection caused breakdown of the blood-brain barrier accompanied by decreased surface expression of tight junction proteins. Furthermore, while the MAV-1-induced pathogenesis and inflammation were dependent on E3, MAV-1-induced breakdown of the blood-brain barrier and alteration of endothelial cell function were not dependent on E3 or CCL2.
 ...
PMID:Mouse adenovirus type 1-induced breakdown of the blood-brain barrier. 1957 Aug 56

The use of allogeneic "universal donor" mesenchymal stromal cells (MSCs) may be a substantial clinical convenience for treatment of autoimmune ailments such as multiple sclerosis. We therefore tested whether allogeneic MSCs can be exploited for treatment of experimental autoimmune encephalomyelitis (EAE) in mice with otherwise intact immune system. Administration of allogeneic Balb/c-derived MSCs to C57Bl/6 mice with pre-established EAE led to a significant decrease in disease score over time comparable to that achieved with syngeneic MSCs, and was correlated with a significant blunting of immune cell infiltration to the spinal cord and reduced circulating levels of interferon-gamma (IFN-gamma) and interleukin-17. Pretreatment of allogeneic MSCs with IFN-gamma increased the expression levels of CCL2 as well as major histocompatibility complex I (MHCI) and MHCII, but also led to complete loss of suppressive activity in vivo that correlated with immune rejection. In conclusion, allogeneic MSCs can suppress the manifestations of EAE, yet retain the potential for alloimmunization.
 ...
PMID:Allogeneic mesenchymal stem cells for treatment of experimental autoimmune encephalomyelitis. 1960 99

Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b+ or CD11c+ APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.
 ...
PMID:Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system. 1970 25


<< Previous 1 2 3 4 5 6 7 8 9 Next >>