CCR4 contributes to the pathogenesis of experimental autoimmune encephalomyelitis by regulating inflammatory macrophage function

Forde, Eileen; Dogan, Rukiye-Nazan E.; Karpus, William J.

doi:10.1016/j.jneuroim.2011.04.008

Cited by 40 publications

(26 citation statements)

References 76 publications

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“…CXCR2 is the receptor of MIP-2 and KC, whereas GCP-2 acts on both receptors CXCR1 and CXCR2. CCR4 and CX3CR1 play important roles in regulating the traffic of peripheral leukocytes to the inflamed CNS [27,28]. During onset of clinical disease (day 11 to 12 after immunization) CXCR1, CXCR2 and CCR4 mRNA levels in the brain and spinal cord were significantly increased compared to naive control mice (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes

Berghmans

Heremans

et al. 2012

J Neuroinflammation

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BackgroundNeutrophil influx is an important sign of hyperacute neuroinflammation, whereas the entry of activated lymphocytes into the brain parenchyma is a hallmark of chronic inflammatory processes, as observed in multiple sclerosis (MS) and its animal models of experimental autoimmune encephalomyelitis (EAE). Clinically approved or experimental therapies for neuroinflammation act by blocking leukocyte penetration of the blood brain barrier. However, in view of unsatisfactory results and severe side effects, complementary therapies are needed. We have examined the effect of chlorite-oxidized oxyamylose (COAM), a potent antiviral polycarboxylic acid on EAE.MethodsEAE was induced in SJL/J mice by immunization with spinal cord homogenate (SCH) or in IFN-γ-deficient BALB/c (KO) mice with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were treated intraperitoneally (i.p.) with COAM or saline at different time points after immunization. Clinical disease and histopathology were compared between both groups. IFN expression was analyzed in COAM-treated MEF cell cultures and in sera and peritoneal fluids of COAM-treated animals by quantitative PCR, ELISA and a bioassay on L929 cells. Populations of immune cell subsets in the periphery and the central nervous system (CNS) were quantified at different stages of disease development by flow cytometry and differential cell count analysis. Expression levels of selected chemokine genes in the CNS were determined by quantitative PCR.ResultsWe discovered that COAM (2 mg i.p. per mouse on days 0 and 7) protects significantly against hyperacute SCH-induced EAE in SJL/J mice and MOG35-55-induced EAE in IFN-γ KO mice. COAM deviated leukocyte trafficking from the CNS into the periphery. In the CNS, COAM reduced four-fold the expression levels of the neutrophil CXC chemokines KC/CXCL1 and MIP-2/CXCL2. Whereas the effects of COAM on circulating blood and splenic leukocytes were limited, significant alterations were observed at the COAM injection site.ConclusionsThese results demonstrate novel actions of COAM as an anti-inflammatory agent with beneficial effects on EAE through cell deviation. Sequestration of leukocytes in the non-CNS periphery or draining of leukocytes out of the CNS with the use of the chemokine system may thus complement existing treatment options for acute and chronic neuroinflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes

Berghmans

Heremans

et al. 2012

J Neuroinflammation

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“…Recent studies have unraveled the mechanism of disease resistance in CCR2 −/− animals by demonstrating a disease-promoting role of CCR2 + Ly-6C high monocytes during induction of EAE (37). During the preparation of this manuscript, it was further suggested that a reduction in the numbers of (TNF-producing) inflammatory macrophages observed in CNS, spleen, and LN were causative for enhanced EAE resistance in CCR4 −/− mice (38). Our data, however, indicate that equal numbers of myeloid cells (including inflammatory macrophages) are present in the peripheral blood of WT or CCR4 −/− mice at various disease stages.…”

Section: Discussionmentioning

confidence: 95%

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Poppensieker

Otte

Schürmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4 −/− mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4 −/− mice, indicating that CCR4 + DCs are cellular mediators of EAE development. Mechanistically, CCR4 −/− DCs were less efficient in GM-CSF and IL-23 production and also T H -17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4 −/− mice, whereas intracerebral inoculation using IL-23 −/− DCs or GM-CSF −/− DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.chemokines | neuroinflammation M ultiple sclerosis (MS) is a chronic demyelinating disease of the human CNS (1). Experimental autoimmune encephalomyelitis (EAE), the animal model of MS, is mediated by myelin-specific CD4 + T cells activated by professional antigenpresenting cells (APCs) in peripheral lymphoid tissues (2, 3). In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4-8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.Chemokines and their G protein-coupled receptors are key regulators of leukocyte trafficking (9, 10). The CC chemokine receptor 4 (CCR4) is the cognate receptor for the CC chemokines CCL17 and CCL22, and is expressed on functionally distinct subsets of T cells, including activated T cells, T H 2 cells, and Treg cells. CCR4 has also been found on platelets, NK cells, macrophages, and DCs (11-15). DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18-20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22). However, it rema...

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“…It has been reported that in EAE up-regulation of CCL2, CCL3, CCL4 induces greater macrophage accumulation and effector function in the CNS [28–30,38]. At EAE onset, CCL22 (monocyte-derived thymus-specific chemokine) is greatly up-regulated in the draining LNs and spinal cord; in contrast, neutralization of CCL22 activity decreases macrophage accumulation in the CNS and causes milder EAE [38].…”

Section: Macrophages In Eaementioning

confidence: 99%

Macrophages: A double-edged sword in experimental autoimmune encephalomyelitis

2014

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Multiple sclerosis (MS) is a debilitating neurological disorder of the central nervous system (CNS), characterized by activation and infiltration of leukocytes and dendritic cells into the CNS. In the initial phase of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), peripheral macrophages infiltrate into the CNS, where, together with residential microglia, they participate in the induction and development of disease. During the early phase, microglia/macrophages are immediately activated to become classically activated macrophages (M1 cells), release pro-inflammatory cytokines and damage CNS tissue. During the later phase, microglia/macrophages in the inflamed CNS are less activated, present as alternatively activated macrophage phenotype (M2 cells), releasing anti-inflammatory cytokines, accompanied by inflammation resolution and tissue repair. The balance between activation and polarization of M1 cells and M2 cells in the CNS is important for disease progression. Pro-inflammatory IFN-[H9253] and IL-12 drive M1 cell polarization, while IL-4 and IL-13 drive M2 cell polarization. Given that polarized macrophages are reversible in a well-defined cytokine environment, macrophage phenotypes in the CNS can be modulated by molecular intervention. This review summarizes the detrimental and beneficial roles of microglia and macrophages in the CNS, with an emphasis on the role of M2 cells in EAE and MS patients.

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CCR4 contributes to the pathogenesis of experimental autoimmune encephalomyelitis by regulating inflammatory macrophage function

Cited by 40 publications

References 76 publications

Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes

Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Macrophages: A double-edged sword in experimental autoimmune encephalomyelitis

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