ORCID Profile
0000-0003-1478-3328
Current Organisation
Hannover Medical School
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Publisher: The American Association of Immunologists
Date: 06-2011
Abstract: Astrocytes are activated in experimental autoimmune encephalomyelitis (EAE) and have been suggested to either aggravate or ameliorate EAE. However, the mechanisms leading to an adverse or protective effect of astrocytes on the course of EAE are incompletely understood. To gain insight into the astrocyte-specific function of gp130 in EAE, we immunized mice lacking cell surface expression of gp130, the signal-transducing receptor for cytokines of the IL-6 family, with myelin oligodendrocyte glycoprotein35–55 peptide. These glial fibrillary acid protein (GFAP)-Cre gp130fl/fl mice developed clinically a significantly more severe EAE than control mice and succumbed to chronic EAE. Loss of astrocytic gp130 expression resulted in apoptosis of astrocytes in inflammatory lesions of GFAP-Cre gp130fl/fl mice, whereas gp130fl/fl control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130fl/fl mice was paralleled by significantly larger areas of demyelination and significantly increased numbers of CD4 T cells in the CNS. Additionally, loss of astrocytes in GFAP-Cre gp130fl/fl mice resulted in a reduction of CNS regulatory Foxp3+ CD4 T cells and an increase of IL-17–, IFN-γ–, and TNF-producing CD4 as well as IFN-γ– and TNF-producing CD8 T cells, illustrating that astrocytes regulate the phenotypic composition of T cells. An analysis of mice deficient in either astrocytic gp130– Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130–STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130–Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130–STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE.
Publisher: Wiley
Date: 27-10-2002
DOI: 10.1002/GLIA.10104
Abstract: The expression and kinetics of a panel of chemokines during Toxoplasma encephalitis (TE) were analyzed in a comparative study of genetically resistant BALB/c and susceptible C57BL/6 mice. In parallel with disease activity and the number of postinfection (p.i.) leukocytes, C57BL/6 mice induced CRG-2/IP-10, MuMIG, RANTES, MCP-1, MIP-1alpha, and MIP-1beta earlier and reached increased levels, as compared with BALB/c mice. These differences in the kinetics of intracerebral (i.c.) chemokines may serve as a compensatory mechanism to prevent death from necrotizing TE in C57BL/6 mice in contrast, BALB/c mice downregulated i.c. chemokines with efficient parasite control in the chronic latent phase. Furthermore, this study showed that the pattern of i.c. chemokines and the cellular sources were identical in both strains of mice, with astrocytes and microglia expressing CRG-2/IP-10 and MCP-1 or RANTES and MuMIG, respectively, and leukocytes transcribing CRG-2/IP-10, MCP-1, and RANTES. Thus, the present study demonstrates that host genetic factors exert a strong impact on i.c. chemokines in experimental murine TE.
Publisher: Springer Science and Business Media LLC
Date: 05-2002
DOI: 10.1007/S00401-001-0491-7
Abstract: The intracerebral formation of inflammatory infiltrates is a complex process, which may be regulated by chemokines. This study defines the kinetics and cellular sources of T cell- and macrophage-attracting chemokines in murine Toxoplasma encephalitis (TE) by ribonuclease protection assay, reverse transcription-PCR, in situ hybridization, and immunohistochemistry. Whereas astrocytes were the major source of interferon (IFN)-gamma-inducible protein-10 (CRG-2/IP-10) and monocyte chemoattractant protein (MCP)-1, microglia expressed RANTES, monokine induced by IFN-gamma (MuMIG) and occasionally CRG-2/IP-10 RNA. Despite being ubiquitously activated, only astrocytes and microglia confined to inflammatory infiltrates expressed chemokine genes. Intracerebral leukocytes transcribed RANTES, MuMIG, and occasionally CRG-2/IP-10 and MCP-1. IFN-gamma-deficient mice failed to produce CRG-2/IP-10, MuMIG, RANTES and expressed macrophage inflammatory protein (MIP-1)alpha, MIP-1 beta, and MCP-1 mRNA at reduced levels, functionally resulting in a strongly reduced recruitment of leukocytes across the blood-brain barrier and prevented their further invasion of the brain parenchyma. Since T cells are the single source of IFN-gamma in TE, these findings indicate that T cells pave the way of leukocytes to parenchymatous parasites via IFN-gamma.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.IJPARA.2010.03.011
Abstract: The inhibition of TNF with therapeutic monoclonal antibodies or antibody/receptor fusion proteins in rheumatoid arthritis still constitutes the benchmark for a successful intervention in an ongoing auto-immune-inflammatory disease and underlines the importance of this cytokine. TNF plays a central role in the defence against intracellular infections and is responsible for the promotion of different aspects of the innate immune response such as inflammatory cell recruitment and cell differentiation. While this cytokine generally displays pro-inflammatory activities supporting the early stages of the inflammatory response, it has been demonstrated to be especially important during infection with intracellular pathogens and, consequently, leishmaniasis of TNF(-/-) mice ends fatally. However, the specific activities of TNF that confer protection are not yet fully understood. This review will summarize the current understanding of TNF function and signalling, and will discuss recent work in the models of malaria, toxoplasmosis, trypanosomiasis and leishmaniasis with particular emphasis on work with gene-deficient mouse models.
Location: Germany
No related grants have been discovered for Dirk Schlüter.