Blood–brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

Schellenberg, Angela E; Buist, Richard; Bigio, Marc R. Del; Toft-Hansen, Henrik; Khorooshi, Reza; Owens, Trevor; Peeling, James

doi:10.1186/2045-8118-9-10

Cited by 31 publications

(26 citation statements)

References 27 publications

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“…Building on previous work demonstrating the importance of CCR2/CCL2 axis in neuroinflammation (20, 22, 29, 31–33, 43, 44), we show for the first time that CCR2 is essential for DC recruitment to the CNS during EAE. Specifically, we show that unlike for monocytes, CCR2 might not be essential for emigration of DC from BM as CCR2−/− DCs were found in blood and spleen in mixed BM chimera mice.…”

Section: Discussionsupporting

confidence: 70%

CCR2-Dependent Dendritic Cell Accumulation in the Central Nervous System during Early Effector Experimental Autoimmune Encephalomyelitis Is Essential for Effector T Cell Restimulation In Situ and Disease Progression

Clarkson

Walker

Harris

et al. 2015

The Journal of Immunology

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Dendritic cells (DCs)—while absent from the healthy CNS parenchyma—rapidly accumulate within brain and spinal cord tissue during neuroinflammation associated with experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis). Yet, while DCs have been appreciated for their role in initiating adaptive immune responses in peripheral lymphoid organ tissues, how DCs infiltrate the CNS and contribute to ongoing neuroinflammation in situ is poorly understood. Here we report that; 1) CD11c+ bone marrow-derived (BM)DCs and CNS-infiltrating DCs express chemokine receptor CCR2, 2) compared to CCR2+/+ cells, adoptively transferred CCR2−/− BMDCs or DC precursors do not accumulate in the CNS during EAE, despite abundance in blood, 3) CCR2−/− DCs show less accumulation in the inflamed CNS in mixed bone marrow chimeras, when compared to CCR2+/+ DCs, and 4) ablation of CCR2+/+ DCs during EAE clinical onset delays progression and attenuates cytokine production by infiltrating T cells. While the role of CCR2 in monocyte migration into the CNS has been implicated previously, the role of CCR2 in DC infiltration into the CNS has never been directly addressed. Our data suggest that CCR2-dependent DC recruitment to the CNS during ongoing neuroinflammation plays a crucial role in effector T cell cytokine production and disease progression, and signify that CNS-DCs and circulating DC precursors might be key therapeutic targets for suppressing ongoing neuroinflammation in CNS autoimmune diseases.

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Section: Discussionsupporting

confidence: 70%

CCR2-Dependent Dendritic Cell Accumulation in the Central Nervous System during Early Effector Experimental Autoimmune Encephalomyelitis Is Essential for Effector T Cell Restimulation In Situ and Disease Progression

Clarkson

Walker

Harris

et al. 2015

The Journal of Immunology

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“…CCR2 signaling contributes to monocyte homeostasis even during non-inflammatory conditions [18]. CCL2 is a chemoattractant molecule that can promote infiltration of monocytes to sites of inflammation including to the brain as demonstrated by our group and others [15, 19-21]. Therefore, we used intracranial injections of rAAV9 virus to over express CCL2 in the mouse hippocampus.…”

Section: Resultsmentioning

confidence: 99%

Adeno associated viral-mediated intraosseous labeling of bone marrow derived cells for CNS tracking

Selenica

Reid

Pena

et al. 2016

Journal of Immunological Methods

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Inflammation, including microglial activation in the CNS, is an important hallmark in many neurodegenerative diseases. Microglial stimuli not only impact the brain microenvironment by production and release of cytokines and chemokines, but also influence the activity of bone marrow derived cells and blood born macrophage populations. In many diseases including brain disorders and spinal cord injury, researchers have tried to harbor the neuroprotective and repair properties of these subpopulations. Hematopoietic bone marrow derived cells (BMDCs) are of great interest, especially during gene therapy because certain hematopoietic cell subpopulations traffic to the sites of injury and inflammation. The aim of this study was to develop a method of labeling endogenous bone marrow derived cells through intraosseus impregnation of recombinant adeno-associated virus (rAAV) or lentivirus. We utilized rAAV serotype 9 (rAAV-9) or lentivirus for gene delivery of green florescence protein (GFP) to the mouse bone marrow cells. Flow cytometry showed that both viruses were able to efficiently transduce mouse bone marrow cells in vivo. However, the rAAV9–GFP viral construct transduced BMDCs more efficiently than the lentivirus (11.2% vs. 6.8%), as indicated by cellular GFP expression. We also demonstrate that GFP labeled cells correspond to bone marrow cells of myeloid origin using CD11b as a marker. Additionally, we characterized the ability of bone marrow derived, GFP labeled cells to extravasate into the brain parenchyma upon acute and subchronic neuroinflammatory stimuli in the mouse CNS. Viral mediated over expression of chemokine (C-C motif) ligand 2 (CCL2) or intracranial injection of lipopolysaccharide (LPS) recruited GFP labeled BMDCs from the periphery into the brain parenchyma compared to vehicle treated mice. Altogether our findings demonstrate a useful method of labeling endogenous BMDCs via viral transduction and the ability to track subpopulations throughout the body following insult or injury. Alternatively, this method might find utility in delivering therapeutic genes for neuroinflammatory conditions.

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“…Notably, however, a recent report describing the effect of pertussis toxin injection in mice constitutively overexpressing CCL2 selectively in oligodendrocytes under direction of the myelin basic protein (MBP) promoter, found no evidence of a disrupted CLN-5 pattern accompanying leukocyte extravasation into brain [44]. This apparent contradiction may be due, in part, to the high level of chronic over-expression of CCL2 (<100,000 times normal values) having caused down-modulation of CCR2, the cognate receptor for CCL2, on BMECs [45], as well as inappropriate or inadequate access of oligodendrocyte-derived CCL2 – normally not found in health or disease – to the CNS microvasculature.…”

Section: Discussionmentioning

confidence: 99%

Cell-selective knockout and 3D confocal image analysis reveals separate roles for astrocyte-and endothelial-derived CCL2 in neuroinflammation

Paul¹,

Ge²,

Lemire³

et al. 2014

J Neuroinflammation

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BackgroundExpression of chemokine CCL2 in the normal central nervous system (CNS) is nearly undetectable, but is significantly upregulated and drives neuroinflammation during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis which is considered a contributing factor in the human disease. As astrocytes and brain microvascular endothelial cells (BMEC) forming the blood–brain barrier (BBB) are sources of CCL2 in EAE and other neuroinflammatory conditions, it is unclear if one or both CCL2 pools are critical to disease and by what mechanism(s).MethodsMice with selective CCL2 gene knockout (KO) in astrocytes (Astro KO) or endothelial cells (Endo KO) were used to evaluate the respective contributions of these sources to neuroinflammation, i.e., clinical disease progression, BBB damage, and parenchymal leukocyte invasion in a myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced EAE model. High-resolution 3-dimensional (3D) immunofluorescence confocal microscopy and colloidal gold immuno-electron microscopy were employed to confirm sites of CCL2 expression, and 3D immunofluorescence confocal microscopy utilized to assess inflammatory responses along the CNS microvasculature.ResultsCell-selective loss of CCL2 immunoreactivity was demonstrated in the respective KO mice. Compared to wild-type (WT) mice, Astro KO mice showed reduced EAE severity but similar onset, while Endo KO mice displayed near normal severity but significantly delayed onset. Neither of the KO mice showed deficits in T cell proliferation, or IL-17 and IFN-γ production, following MOG35-55 exposure in vitro, or altered MOG-major histocompatibility complex class II tetramer binding. 3D confocal imaging further revealed distinct actions of the two CCL2 pools in the CNS. Astro KOs lacked the CNS leukocyte penetration and disrupted immunostaining of CLN-5 at the BBB seen during early EAE in WT mice, while Endo KOs uniquely displayed leukocytes stalled in the microvascular lumen.ConclusionsThese results point to astrocyte and endothelial pools of CCL2 each regulating different stages of neuroinflammation in EAE, and carry implications for drug delivery in neuroinflammatory disease.

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Blood–brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

Cited by 31 publications

References 27 publications

CCR2-Dependent Dendritic Cell Accumulation in the Central Nervous System during Early Effector Experimental Autoimmune Encephalomyelitis Is Essential for Effector T Cell Restimulation In Situ and Disease Progression

CCR2-Dependent Dendritic Cell Accumulation in the Central Nervous System during Early Effector Experimental Autoimmune Encephalomyelitis Is Essential for Effector T Cell Restimulation In Situ and Disease Progression

Adeno associated viral-mediated intraosseous labeling of bone marrow derived cells for CNS tracking

Cell-selective knockout and 3D confocal image analysis reveals separate roles for astrocyte-and endothelial-derived CCL2 in neuroinflammation

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