Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system

Milner, Richard; Campbell, Iain L.

doi:10.1016/j.mcn.2006.09.004

Cited by 49 publications

(46 citation statements)

References 58 publications

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“…The microenvironment of the cerebellum in the GFAP-IL6 mice is characterized by chronic activation of the vascular endothelium. In particular, the levels of the cellular adhesion molecules ICAM-1 and VCAM-1 as well as a number of integrins is increased significantly on vascular endothelium (19,38). This pre-existing activation state of the vascular endothelium in the cerebellum of the GFAP-IL6 mice would be expected to favor the increased adhesion and subsequent transendothelial migration of leukocytes following MOG-immunization.…”

Section: Discussionmentioning

confidence: 97%

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Quintana¹,

Müller²,

Frausto³

et al. 2009

The Journal of Immunology

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107

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IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-γ and TNF-α mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte “sink” that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.

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Section: Discussionmentioning

confidence: 97%

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Quintana¹,

Müller²,

Frausto³

et al. 2009

The Journal of Immunology

Self Cite

107

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“…One possibility is that MECA-32 expression reflects altered activation status of brain endothelial cells, akin to induction of VCAM-1 and ICAM-1, and that MECA-32 expression is part of a stress-induced early response common to hypoxia and inflammation. Alternatively, as angiogenesis often accompanies inflammation (Campbell et al, 1993;Milner and Campbell, 2006), induction of the MECA-32 antigen may represent early angiogenic events associated with inflammation.…”

Section: Temporal Expression Pattern Of Fibronectin α5 Integrin and mentioning

confidence: 99%

Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia

Milner

Hung

Erokwu

et al. 2008

Molecular and Cellular Neuroscience

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120

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The extracellular matrix (ECM) is an important regulator of angiogenesis and vascular remodeling. We showed previously that angiogenic capillaries in the developing CNS express high levels of fibronectin and its receptor α5β1 integrin, and that this expression is developmentally downregulated. As cerebral hypoxia leads to an angiogenic response, we sought to determine whether angiogenic vessels in the adult CNS re-express fibronectin and the α5β1 integrin. Ten-week old mice were subject to hypobaric hypoxia for 0, 4, 7 and 14 days, and fibronectin/integrin expression examined. Fibronectin and the α5 integrin subunit were strongly upregulated on capillaries in the hypoxic CNS, with the effect maximal at the earliest time point examined (4 days). Immunofluorescent studies demonstrated that the α5 integrin was expressed by angiogenic endothelial cells. In light of the defined angiogenic role for fibronectin in other systems, this work suggests that induction of fibronectin-α5β1 integrin expression may be an important molecular switch driving angiogenesis in the hypoxic CNS.

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“…Microglia on an LN substrate adopt a less activated, poorly adhesive phenotype and show reduced levels of expression of the activation markers (32). It has also been shown that microglial adhesion to LN is mediated entirely by the ␣6␤1 integrin, and microglial adhesion to LN was increased significantly by the proinflammatory cytokines (6,33). However, cytokines did not change ␣6␤1 expression levels but altered the activation state of ␣6␤1, mediated by a PKC-dependent mechanism.…”

Section: Discussionmentioning

confidence: 98%

Regulation of Integrin α6 Recycling by Calcium-independent Phospholipase A2 (iPLA2) to Promote Microglia Chemotaxis on Laminin

Lee

Sud

Lee

et al. 2016

Journal of Biological Chemistry

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Microglia are the immune effector cells that are activated in response to pathological changes in the central nervous system. Microglial activation is accompanied by the alteration of integrin expression on the microglia surface. However, changes of integrin expression upon chemoattractant (ADP) stimulation still remain unknown. In this study, we investigated whether ADP induces the alteration of integrin species on the cell surface, leading to changes in chemotactic ability on different extracellular matrix proteins. Flow cytometry scans and on-cell Western assays showed that ADP stimulation induced a significant increase of ␣6 integrin-GFP, but not ␣5, on the surface of microglia cells. Microglia also showed a greater motility increase on laminin than fibronectin after ADP stimulation. Time lapse microscopy and integrin endocytosis assay revealed the essential role of calcium-independent phospholipase A 2 activity for the recycling of ␣6 integrin-GFP from the endosomal recycling complex to the plasma membrane. Lack of calcium-independent phospholipase A 2 activity caused a reduced rate of focal adhesion formation on laminin at the leading edge. Our results suggest that the alteration of integrin-mediated adhesion may regulate the extent of microglial infiltration into the site of damage by controlling their chemotactic ability.Microglia are the immune effector cells in the central nervous system (CNS). Under normal conditions, microglia exist as nonmigratory ramified cells. The ramified morphology of resting microglia is rapidly transformed into a motile ameboid form after pathological stimuli, driving the migration of microglia cells toward lesion sites (1-3). There is a growing body of evidence that the extracellular matrix (ECM) 2 and integrins are important for modulating microglial behavior. ECM influences microglial behavior as fibronectin (FN) and laminin (LN) often show opposite effects on microglial morphology, adhesion, and activation. FN promotes transformation of amoeboid microglia into ramified microglia, whereas LN causes the reverse transformation (4). FN also promotes increased secretion of amyloid precursor protein by microglial cells, whereas LN and collagen have the opposite effect (5). It has been demonstrated that microglia attach strongly to FN and vitronectin but only weakly to LN and astrocyte ECM and that LN exerts a dominant antiadhesive effect on microglial adhesion (6

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Increased expression of the β4 and α5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-α in the central nervous system

Cited by 49 publications

References 58 publications

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia

Regulation of Integrin α6 Recycling by Calcium-independent Phospholipase A2 (iPLA2) to Promote Microglia Chemotaxis on Laminin

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