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TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain.

McColl A, Thomson CA, Nerurkar L, Graham GJ, Cavanagh J - J Neuroinflammation (2016)

Bottom Line: Here we use a well-characterised animal model of psoriasis-like skin inflammation-imiquimod-to investigate the effects of tissue-specific peripheral inflammation on the brain.We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5).Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection, Immunity & Inflammation, College of Medical & Veterinary Life Sciences, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.

ABSTRACT

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders.

Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation-imiquimod-to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour.

Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity.

Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response.

No MeSH data available.


Related in: MedlinePlus

Aldara treatment induces the infiltration of CD3+ cells into the brain. Mice were treated with 80-mg Aldara cream or control cream every 24 h for one, three or five consecutive days. Mice were euthanised 24 h following the final application. Perfused brains were fixed in formalin and embedded in paraffin before being sectioned to 7 μm. a Three sections from each brain were stained for CD3. Representative sections of the hippocampus and cerebellum are shown at ×400 magnification or ×100 magnification (□). Arrows indicate CD3+ cells. b Whole brain CD3+ infiltrates were counted blind. n = 4 mice per group. Significance was determined using two-way ANOVA with Bonferroni multiple comparison post-tests ***p ≤ 0.001
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Fig6: Aldara treatment induces the infiltration of CD3+ cells into the brain. Mice were treated with 80-mg Aldara cream or control cream every 24 h for one, three or five consecutive days. Mice were euthanised 24 h following the final application. Perfused brains were fixed in formalin and embedded in paraffin before being sectioned to 7 μm. a Three sections from each brain were stained for CD3. Representative sections of the hippocampus and cerebellum are shown at ×400 magnification or ×100 magnification (□). Arrows indicate CD3+ cells. b Whole brain CD3+ infiltrates were counted blind. n = 4 mice per group. Significance was determined using two-way ANOVA with Bonferroni multiple comparison post-tests ***p ≤ 0.001

Mentions: Together, these data characterise the significant lymphoid infiltrate into the brain following cutaneous Aldara treatment and implicate brain-resident cells as an initial source of the T cell chemoattractant CXCL10. Surprisingly, histological examination of CD3 expression in the brain revealed that, rather than being localised to perivascular cuffs, CD3+ cells were scattered throughout the brain parenchyma (Fig. 6a). There was no anatomical specificity to the infiltrating cells as they were present throughout the parenchyma, as well as around specific brain regions including the cerebellum, hippocampus and circumventricular organs (CVOs). Consistent with the flow cytometry data, there were elevated numbers of CD3+ cells at day 3 and day 5 following Aldara treatment (Fig. 6b).Fig. 6


TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain.

McColl A, Thomson CA, Nerurkar L, Graham GJ, Cavanagh J - J Neuroinflammation (2016)

Aldara treatment induces the infiltration of CD3+ cells into the brain. Mice were treated with 80-mg Aldara cream or control cream every 24 h for one, three or five consecutive days. Mice were euthanised 24 h following the final application. Perfused brains were fixed in formalin and embedded in paraffin before being sectioned to 7 μm. a Three sections from each brain were stained for CD3. Representative sections of the hippocampus and cerebellum are shown at ×400 magnification or ×100 magnification (□). Arrows indicate CD3+ cells. b Whole brain CD3+ infiltrates were counted blind. n = 4 mice per group. Significance was determined using two-way ANOVA with Bonferroni multiple comparison post-tests ***p ≤ 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4862138&req=5

Fig6: Aldara treatment induces the infiltration of CD3+ cells into the brain. Mice were treated with 80-mg Aldara cream or control cream every 24 h for one, three or five consecutive days. Mice were euthanised 24 h following the final application. Perfused brains were fixed in formalin and embedded in paraffin before being sectioned to 7 μm. a Three sections from each brain were stained for CD3. Representative sections of the hippocampus and cerebellum are shown at ×400 magnification or ×100 magnification (□). Arrows indicate CD3+ cells. b Whole brain CD3+ infiltrates were counted blind. n = 4 mice per group. Significance was determined using two-way ANOVA with Bonferroni multiple comparison post-tests ***p ≤ 0.001
Mentions: Together, these data characterise the significant lymphoid infiltrate into the brain following cutaneous Aldara treatment and implicate brain-resident cells as an initial source of the T cell chemoattractant CXCL10. Surprisingly, histological examination of CD3 expression in the brain revealed that, rather than being localised to perivascular cuffs, CD3+ cells were scattered throughout the brain parenchyma (Fig. 6a). There was no anatomical specificity to the infiltrating cells as they were present throughout the parenchyma, as well as around specific brain regions including the cerebellum, hippocampus and circumventricular organs (CVOs). Consistent with the flow cytometry data, there were elevated numbers of CD3+ cells at day 3 and day 5 following Aldara treatment (Fig. 6b).Fig. 6

Bottom Line: Here we use a well-characterised animal model of psoriasis-like skin inflammation-imiquimod-to investigate the effects of tissue-specific peripheral inflammation on the brain.We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5).Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection, Immunity & Inflammation, College of Medical & Veterinary Life Sciences, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.

ABSTRACT

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders.

Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation-imiquimod-to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour.

Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity.

Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response.

No MeSH data available.


Related in: MedlinePlus