Complement C5 in Experimental Autoimmune Encephalomyelitis (EAE) Facilitates Remyelination and Prevents Gliosis

Weerth, Susanna; Rus, Horea; Shin, Moon L.; Raine, Cedric S.

doi:10.1016/s0002-9440(10)63466-9

Cited by 61 publications

(52 citation statements)

References 59 publications

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“…The specificities for anti-VCAM1 and anti-TIE2 antibodies have been shown previously (Weerth et al, 2003;Cho et al, 2004, respectively). Acetonefixed cryosections were used for anti-PECAM1 and anti-TIE2 staining, whereas PFA-fixed, deparaffinized sections were used for anti-VCAM1-and anti-HIF1␣-staining.…”

Section: Immunohistochemistry and Immunoblottingsupporting

confidence: 57%

Redundant roles ofSox17andSox18in postnatal angiogenesis in mice

Matsui

Kanai‐Azuma

Hara

et al. 2006

Journal of Cell Science

181

168

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Sox7, Sox17 and Sox18 constitute group F of the Sox family of HMG box transcription factor genes. Dominant-negative mutations in Sox18 underlie the cardiovascular defects observed in ragged mutant mice. By contrast, Sox18-/- mice are viable and fertile, and display no appreciable anomaly in their vasculature, suggesting functional compensation by the two other SoxF genes. Here, we provide direct evidence for redundant function of Sox17 and Sox18 in postnatal neovascularization by generating Sox17+/--Sox18-/- double mutant mice. Whereas Sox18-/- and Sox17+/--Sox18+/- mice showed no vascular defects, approximately half of the Sox17+/--Sox18-/- pups died before postnatal day 21 (P21). They showed reduced neovascularization in the liver sinusoids and kidney outer medulla vasa recta at P7, which most likely caused the ischemic necrosis observed by P14 in hepatocytes and renal tubular epithelia. Those that survived to adulthood showed similar, but milder, vascular anomalies in both liver and kidney, and females were infertile with varying degrees of vascular abnormalities in the reproductive organs. These anomalies corresponded with sites of expression of Sox7 and Sox17 in the developing postnatal vasculature. In vitro angiogenesis assays, using primary endothelial cells isolated from the P7 livers, showed that the Sox17+/--Sox18-/- endothelial cells were defective in endothelial sprouting and remodeling of the vasculature in a phenotype-dependent manner. Therefore, our findings indicate that Sox17 and Sox18, and possibly all three SoxF genes, are cooperatively involved in mammalian vascular development.

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Section: Immunohistochemistry and Immunoblottingsupporting

confidence: 57%

Redundant roles ofSox17andSox18in postnatal angiogenesis in mice

Matsui

Kanai‐Azuma

Hara

et al. 2006

Journal of Cell Science

181

168

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“…Expression of this receptor has also been reported on neurons and astrocytes (Gasque et al, 1995;Van Beek et al, 2000). The dual role of C5 in enhancement of inflammatory demyelination in acute EAE and promoting remyelination in recovery in the CNS has been recently proposed (Weerth et al, 2003). Furthermore, it was shown that the C5 complement component can protect oligodendrocytes from apoptosis in the recovery phase of EAE (Niculescu et al, 2004).…”

Section: Discussionmentioning

confidence: 93%

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist

Sewell

Nacewicz

Liu

et al. 2004

Journal of Neuroimmunology

123

111

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The role of complement components in traumatic brain injury is poorly understood. Here we show that secondary damage after acute cryoinjury is significantly reduced in C3 −/− or C5 −/− mice or in mice treated with C5a receptor antagonist peptides. Injury sizes and neutrophil extravasation were compared. While neutrophil density increased following traumatic brain injury in wild type (C57BL/6) mice, C3-deficient mice demonstrated lower neutrophil extravasation and injury sizes in the brain. RNase protection assay indicated that C3 contributes to the induction of brain inflammatory mediators, MIF, RANTES (CCL5) and MCP-1 (CCL2). Intracranial C3 injection induced neutrophil extravasation in injured brains of C3 −/− mice suggesting locally produced C3 is important in brain inflammation. We show that neutrophil extravasation is significantly reduced in both C5 −/− mice and C5a receptor antagonist treated cryoinjured mice suggesting that one of the possible mechanisms of C3 effect on neutrophil extravasation is mediated via downstream complement activation products such as C5a. Our data indicates that complement inhibitors may ameliorate traumatic brain injury.

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“…CR3 or Mac-1) attenuates the severity of EAE and reduces leukocyte infiltration into the CNS, while transgenic expression of C3a in the CNS markedly exacerbates EAE (Boos et al, 2004;Bullard et al, 2005;Nataf et al, 2000). In contrast deletion of C5, C5-derived fragments, and their associated receptors has no effect on the course of EAE (Reiman et al, 2002;Reiman et al, 2005;Weerth et al, 2003). Pharmacological inhibition of the C5a receptor also fails to lessen the severity of EAE (Morgan et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease

Szalai

Adams

et al. 2007

Molecular Immunology

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Complement per se has been shown to play an important role in demyelinating disease but controversy remains regarding the role of C3 in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In this study we used C3 -/-mice to confirm previous findings that C3 is required for full development of EAE. Furthermore, C3 +/-mice (with serum C3 levels 50% that of wild type mice) developed EAE with a severity intermediate between wild type and C3 -/-mice. Importantly transfer of wild type encephalitogenic T cells to C3 -/-mice resulted in attenuated EAE. C3 -/-mice with EAE had fewer CD4 + and CD8 + T cells in the CNS and 50% fewer of these cells produced IFN-γ compared to wild type mice. When treated with anti-CD3 antibody, CD4 + T cell from wild type and C3 -/-mice had similar activation profiles as judged by IFN-γ production and CD25 and CD69 expression, indicating there is no gross or intrinsic defect in T cells from C3 -/-mice. T cells from primed C3 -/-mice proliferated comparably to that of control T cells on re-stimulation with MOG peptide. Our results confirm a requirement for C3 for maximal development of EAE and suggest that receptors for C3-derived activation fragments might be a viable therapeutic target for prevention and treatment demyelinating disease.

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Complement C5 in Experimental Autoimmune Encephalomyelitis (EAE) Facilitates Remyelination and Prevents Gliosis

Cited by 61 publications

References 59 publications

Redundant roles ofSox17andSox18in postnatal angiogenesis in mice

Redundant roles ofSox17andSox18in postnatal angiogenesis in mice

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist

Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease

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