Early activation of microglia in the pathogenesis of fatal murine cerebral malaria

Medana, Isabelle M.; Hunt, Nicholas H.; Chan‐Ling, Tailoi

doi:10.1002/(sici)1098-1136(199702)19:2<91::aid-glia1>3.0.co;2-c

Cited by 95 publications

(81 citation statements)

References 58 publications

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“…However, in FMCM, glial activation occurs early and is thought to contribute to the increased permeability of the BBB because this occurs well before the onset of symptoms (7). Both astrocytes and microglia become activated and lose their even distribution around cerebral microvessels (68,69), and may contribute to FMCM through the production of proinflammatory mediators (70). The specific pattern of chemokine expression during FMCM (CXCL9 by microglia, CXCL10 by astrocytes) supports previous findings that these are differentially expressed by CNS cells during inflammatory diseases (71)(72)(73) and may not share redundant functions (74 -76).…”

Section: Discussionmentioning

confidence: 99%

Chemokine Gene Expression during Fatal Murine Cerebral Malaria and Protection Due to CXCR3 Deficiency

Miu

Mitchell

Müller

et al. 2008

The Journal of Immunology

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139

170

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Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. Using murine models of malaria, we found much greater up-regulation of a number of chemokine mRNAs, including those for CXCR3 and its ligands, in the brain during fatal murine CM (FMCM) than in a model of non-CM. Expression of CXCL9 and CXCL10 RNA was localized predominantly to the cerebral microvessels and in adjacent glial cells, while expression of CCL5 was restricted mainly to infiltrating lymphocytes. The majority of mice deficient in CXCR3 were found to be protected from FMCM, and this protection was associated with a reduction in the number of CD8+ T cells in brain vessels as well as reduced expression of perforin and FasL mRNA. Adoptive transfer of CD8+ cells from C57BL/6 mice with FMCM abrogated this protection in CXCR3−/− mice. Moreover, there were decreased mRNA levels for the proinflammatory cytokines IFN-γ and lymphotoxin-α in the brains of mice protected from FMCM. These data suggest a role for CXCR3 in the pathogenesis of FMCM through the recruitment and activation of pathogenic CD8+ T cells.

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Section: Discussionmentioning

confidence: 99%

Chemokine Gene Expression during Fatal Murine Cerebral Malaria and Protection Due to CXCR3 Deficiency

Miu

Mitchell

Müller

et al. 2008

The Journal of Immunology

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139

170

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“…Retinal whole mounts (n ϭ 6) were processed as described previously (48) and then incubated in GS isolectin peroxidase conjugate (Sigma-Aldrich) for 4 h. The retinas were processed as reported previously (49,50).…”

Section: Gs Isolectin Conjugated To Hrpmentioning

confidence: 99%

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Chang

Chan‐Ling

McFarland

et al. 2007

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

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128

106

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We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit ؉ ), stem cell antigen-1 (sca-1 ؉ ), hematopoietic stem cell (HSC), or CD34 ؉ endothelial precursor cell (EPC) function. Exposure of CD34 ؉ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygeninduced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions. IGFBP3 ͉ angiogenesis ͉ retinopathy of prematurity V ascular damage associated with diabetic retinopathy and retinopathy of prematurity (ROP) results from tissue ischemia, and, subsequently, this ischemia leads to development of pathological neovascularization. Insulin-like growth factor 1 (IGF1) is required for normal retinal vascular development because vascular development is arrested in its absence despite the presence of VEGF (1). Development of ROP is associated with low levels of IGF1 (2) because the lack of IGF1 in the early neonatal period leads to the development of avascular retina, which results in ROP (3). However, unregulated IGF1 expression can lead to pathological neovascularization (4-13), and IGF1 receptor (IGF1R) antagonists are able to suppress retinal neovascularization in vivo by inhibiting VEGF signaling (1).The effects of IGF1 are mediated by IGF1R and modulated by complex interactions with IGF binding proteins (IGFBPs), which are also modulated at multiple levels. Six IGFBPs function as transporter proteins and storage pools for IGF1 in a tissue-and developmental stage-specific manner. Phosphorylation, proteolysis, polymerization (8), and cell or matrix association (9) regulates the functions of IGFBPs. Specific IGFBPs have been shown to either stimulate or inhibit IGF1 action (10).IGFBP3, the best studied and most abundant of these binding proteins, carries Ն75% of serum IGF1 and IGF2 in heterotrimeric complexes. Besides its endocrine effects, IGFBP3 has auto-and paracrine actions affecting cell mobility, adhesion, apoptosis, survival, and the cell cycle (14,15). Like the other IGFBPs, IGFBP3 has IGF1-in...

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“…They can be activated in response to a wide range of injuries that trigger brain inflammatory responses, including head injury and ischemia, neurodegenerative and autoimmune diseases, viral and bacterial infections, prion diseases, and brain tumors (Sasaki et al 1993; for reviews, see Dubois-Dalcq et al 1995;McGeer and McGeer 1995;Kreutzberg 1996). Microglia may also play a role in host defense against some protozoa, such as Plasmodium (Medana et al 1997(Medana et al ,2000, or against others that affect the immunocompromised host, such as Toxoplasma gondii (Rozenfeld et al 2003; for review, see Suzuki 2002). In addition to these relatively well-known parasites that invade the neural tissue, others, such as Leishmania , have become objects of concern by virtue of reports on the presence of anti-Leishmania antibodies and/or Leishmania amastigotes in the cerebrospinal fluid or of meningeal affection in naturally infected humans and animals (Garcia-Alonso et al 1996;Nieto et al 1996;Prasad and Sen 1996;Vinuelas et al 2001) plus transmission from infected patients to experimental animals under conditions that simulate needle sharing (Morillas-Marquez et al 2002).…”

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confidence: 99%

Destiny and Intracellular Survival ofLeishmania amazonensisin Control and Dexamethasone-treated Glial Cultures: Protozoa-specific Glycoconjugate Tagging and TUNEL Staining

Baetas‐da‐Cruz

Macedo-Silva

Santos-Silva

et al. 2004

J Histochem Cytochem.

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S U M M A R Y Leishmania amazonensis, an obligatory intracellular parasite, survives internalization by macrophages, but no information is available on the involvement of microglia. We have investigated microglia-protozoa interactions in mixed glial cultures infected with promastigote forms of L. amazonensis after lipopolysaccharide (LPS) or dexamethasone (DM) treatment. After 2 hr of exposure to parasites in control cultures, there was a small number of infected microglia (1%). Preincubation with LPS or DM led to 14% or 60% of microglial cells with attached parasites, respectively. DM treatment resulted in 39% of microglial cells with internalized parasites (controls or LPS-treated cells had Յ 1%). Scanning electron micrographs showed numerous filopodia in DM-treated cells, whereas these projections were rarely observed in LPS-treated or control cells. DM treatment also affected the intramicroglial survival of Leishmania . In control cultures, internalized parasites, tagged with an anti-lipophosphoglycan (anti-LPG) antibody, showed fragmented DNA [terminal deoxyribonucleotide transferase-mediated dUTP-X nick end labeling (TUNEL ϩ )] after 4 hr of interaction, but changes seemed slightly delayed in DM-treated cultures. After 12 hr, there were no LPG ϩ /TUNEL ϩ profiles in controls, whereas rare LPG ϩ profiles still persisted in DM-treated cells. Our results suggest that microglia are highly effective in the elimination of Leishmania and that the process can be effectively studied by LPG/TUNEL double labeling.

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Early activation of microglia in the pathogenesis of fatal murine cerebral malaria

Cited by 95 publications

References 58 publications

Chemokine Gene Expression during Fatal Murine Cerebral Malaria and Protection Due to CXCR3 Deficiency

Chemokine Gene Expression during Fatal Murine Cerebral Malaria and Protection Due to CXCR3 Deficiency

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development

Destiny and Intracellular Survival ofLeishmania amazonensisin Control and Dexamethasone-treated Glial Cultures: Protozoa-specific Glycoconjugate Tagging and TUNEL Staining

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