Endothelial NOS‐deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis

Wu, Muzhou; Tsirka, Stella E.

doi:10.1002/glia.20842

Cited by 38 publications

(41 citation statements)

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“…Tonic eNOS activity controls vascular tone and leukocyte trafficking in the resting state, whereas the activated form drives permeability and extravasation in disease (58). The phenotype of eNOS mutants combines inactivation of the tonic and activated forms and produces complex findings in EAE and carrageenaninduced inflammation (59). Understanding the translational potential of eNOS has been facilitated by development of selective inhibitors, notably cavtratin, a cell-permeable recombinant consisting of the eNOS-binding domain of caveolin-1 coupled to the homeodomain of Drosophila antennapedia (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease

Argaw¹,

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease

Argaw¹,

et al. 2012

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“…Macrophages and activated microglia play important roles in modulating T-cell functions during EAE [31,78,79] . M1 macrophages express high levels of MHC class II and CD86, which are important in antigen presentation.…”

Section: Modulating Leukocyte Functionmentioning

confidence: 99%

Polarization of macrophages and microglia in inflammatory demyelination

Cao

2013

Neurosci. Bull.

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Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, and microglia and macrophages play important roles in its pathogenesis. The activation of microglia and macrophages accompanies disease development, whereas depletion of these cells significantly decreases disease severity. Microglia and macrophages usually have diverse and plastic phenotypes. Both pro-inflammatory and antiinflammatory microglia and macrophages exist in MS and its animal model, experimental autoimmune encephalomyelitis. The polarization of microglia and macrophages may underlie the differing functional properties that have been reported. in this review, we discuss the responses and polarization of microglia and macrophages in MS, and their effects on its pathogenesis and repair. Harnessing their beneficial effects by modulating their polarization states holds great promise for the treatment of inflammatory demyelinating diseases.Keywords: macrophage; microglia; polarization; demyelination; remyelination IntroductionMultiple sclerosis (MS) is a chronic autoimmune inflammatory and demyelinating disease characterized by inflammation, demyelination, axonal damage, gliosis and destruction of the blood-brain barrier [1][2][3] . Although the T-helper (Th) cells Th-1 and Th-17 were thought to be the main response effectors for autoimmune inflammation, macrophages and microglia do play an important role in the pathogenesis of MS. The pathology of newly-forming lesions in relapsingremitting MS shows only microglial activation and macrophage infiltration in demyelinating areas, with rare lymphocyte infiltration [4,5] . Moreover, macrophage depletion and microglial paralysis significantly suppress the progress of experimental autoimmune encephalomyelitis (EAE), the animal model of MS [6,7] .Macrophages and microglia play important roles in bridging the innate and adaptive immune reponses. Under normal physiological conditions, macrophages monitor the tissue environment for pathogens, maintain tissue homeostasis, phagocytose dead and dying cells, and respond rapidly to perturbations in the local environment. Microglia share many phenotypic and functional characteristics with macrophages. in the adult central nervous system (CNS), microglia are on constant surveillance for perturbations resulting from injury or disease [8] . In MS, in which pro-inflammatory, neurotoxic and myelin-attacking microglia and macrophages predominate, some microglia and macrophages with anti-inflammatory, neuroprotective and remyelinationpromoting properties are also present [9] . These conflicting lines of evidence have led to confusion and considerable debate regarding the harmful versus the beneficial roles of macrophages and microglia in MS.The polarization of macrophages and microglia may underlie their differing functional properties. Taking advantage of their beneficial effects by modulating their polarization states holds great promise for the treatment of CNS demyelinating diseases [10][11][12][13] . in this review, we discuss the ...

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“…In vivo permeability assays were performed as described previously with minor modifications (Ohno et al, 1980;Parathath et al, 2006;Wu and Tsirka, 2009;Yepes et al, 2003). Briefly, wild-type (C57BL6, wt), MCP1…”

Section: In Vivo Permeability Assaymentioning

confidence: 99%

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

Yao

Tsirka

2011

Journal of Cell Science

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102

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SummaryPrevious studies have shown that plasmin cleaves monocyte chemoattractant protein 1 (MCP1; officially known as C-C motif chemokine 2, CCL2) at K104, and this cleavage enhances its chemotactic potency significantly. Accumulating evidence reveals that MCP1 also disrupts the integrity of the blood-brain barrier (BBB). Here, we show that K104Stop-MCP1, truncated at the K104 where plasmin would normally cleave, is more efficient than the full-length protein (FL-MCP1) in compromising the integrity of the BBB in in vitro and in vivo models. K104Stop-MCP1 increases the permeability of BBB in both wild-type mice and mice deficient for tissue plasminogen activator (tPA), which converts plasminogen into active plasmin, suggesting that plasmin-mediated truncation of MCP1 plays an important role in BBB compromise. Furthermore, we show that the mechanisms underlying MCP1-induced BBB disruption involve redistribution of tight junction proteins (occludin and ZO-1) and reorganization of the actin cytoskeleton. Finally, we show that the redistribution of ZO-1 is mediated by phosphorylation of ezrin-radixin-moesin (ERM) proteins. These findings identify plasmin as a key signaling molecule in the regulation of BBB integrity and suggest that plasmin inhibitors might be used to modulate diseases accompanied by BBB compromise.

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Endothelial NOS‐deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis

Cited by 38 publications

References 64 publications

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease

Polarization of macrophages and microglia in inflammatory demyelination

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

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