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A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.

Arima Y, Kamimura D, Atsumi T, Harada M, Kawamoto T, Nishikawa N, Stofkova A, Ohki T, Higuchi K, Morimoto Y, Wieghofer P, Okada Y, Mori Y, Sakoda S, Saika S, Yoshioka Y, Komuro I, Yamashita T, Hirano T, Prinz M, Murakami M - Elife (2015)

Bottom Line: Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood.Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse.Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

ABSTRACT
Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.

No MeSH data available.


Related in: MedlinePlus

MHC class II+CD11b+ cells in the CNS of EAE-recovered mice expressed TNFα and IL-1β.Expression of TNFα, and IL-1β in MHC class II+CD11b+ cells in the L5 cord of EAE-recovered mice (n = 3 per group). Mean scores ± SEM are shown. *, p < 0.05; **, p < 0.01. Experiments were performed at least 3 times; representative data are shown.DOI:http://dx.doi.org/10.7554/eLife.08733.015
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fig6s1: MHC class II+CD11b+ cells in the CNS of EAE-recovered mice expressed TNFα and IL-1β.Expression of TNFα, and IL-1β in MHC class II+CD11b+ cells in the L5 cord of EAE-recovered mice (n = 3 per group). Mean scores ± SEM are shown. *, p < 0.05; **, p < 0.01. Experiments were performed at least 3 times; representative data are shown.DOI:http://dx.doi.org/10.7554/eLife.08733.015

Mentions: The fourth and final step is mediated by excessive chemokine expressions and is most likely triggered by the activation of the accumulated pathogenic CD4+ T cells in the third step. Pathogenic CD4+ T cells transferred into mice include Th17 and Th1 cells and express various cytokines beyond IL-17 and IFNγ, including IL-6, TNFα, etc., all of which are stimulators of NFkB and STATs (Ogura et al., 2008; Lee et al., 2012; Murakami et al., 2013; Atsumi et al., 2014). Moreover, we have previously shown that endothelial cells express IL-6 after norepinephrine stimulation (Arima et al., 2012) and MHC class II+CD11b+ cells in the CNS of EAE-recovered mice expressed various cytokines (Figure 6—figure supplement 1). Therefore, we suggest that the local chemokine expression at L5 ventral vessels via various cytokines subsequently enhances an accumulation of immune cells, as shown in Figure 4A. Indeed, we found blockades of IL-6, IL-17A, or CCL20 signals suppressed EAE relapse (Figure 6H,I, and data not shown). The excessive chemokine induction results in excess immune cell migration, which compromises local homeostasis and can trigger inflammatory diseases. Thus, accumulation of both MHC class II+CD11b+ cells and pathogenic CD4+ T cells at the ventral vessels of the L5 cord stimulate the excessive expression of chemokines in non-immune cells to trigger the EAE relapse.


A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.

Arima Y, Kamimura D, Atsumi T, Harada M, Kawamoto T, Nishikawa N, Stofkova A, Ohki T, Higuchi K, Morimoto Y, Wieghofer P, Okada Y, Mori Y, Sakoda S, Saika S, Yoshioka Y, Komuro I, Yamashita T, Hirano T, Prinz M, Murakami M - Elife (2015)

MHC class II+CD11b+ cells in the CNS of EAE-recovered mice expressed TNFα and IL-1β.Expression of TNFα, and IL-1β in MHC class II+CD11b+ cells in the L5 cord of EAE-recovered mice (n = 3 per group). Mean scores ± SEM are shown. *, p < 0.05; **, p < 0.01. Experiments were performed at least 3 times; representative data are shown.DOI:http://dx.doi.org/10.7554/eLife.08733.015
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4530187&req=5

fig6s1: MHC class II+CD11b+ cells in the CNS of EAE-recovered mice expressed TNFα and IL-1β.Expression of TNFα, and IL-1β in MHC class II+CD11b+ cells in the L5 cord of EAE-recovered mice (n = 3 per group). Mean scores ± SEM are shown. *, p < 0.05; **, p < 0.01. Experiments were performed at least 3 times; representative data are shown.DOI:http://dx.doi.org/10.7554/eLife.08733.015
Mentions: The fourth and final step is mediated by excessive chemokine expressions and is most likely triggered by the activation of the accumulated pathogenic CD4+ T cells in the third step. Pathogenic CD4+ T cells transferred into mice include Th17 and Th1 cells and express various cytokines beyond IL-17 and IFNγ, including IL-6, TNFα, etc., all of which are stimulators of NFkB and STATs (Ogura et al., 2008; Lee et al., 2012; Murakami et al., 2013; Atsumi et al., 2014). Moreover, we have previously shown that endothelial cells express IL-6 after norepinephrine stimulation (Arima et al., 2012) and MHC class II+CD11b+ cells in the CNS of EAE-recovered mice expressed various cytokines (Figure 6—figure supplement 1). Therefore, we suggest that the local chemokine expression at L5 ventral vessels via various cytokines subsequently enhances an accumulation of immune cells, as shown in Figure 4A. Indeed, we found blockades of IL-6, IL-17A, or CCL20 signals suppressed EAE relapse (Figure 6H,I, and data not shown). The excessive chemokine induction results in excess immune cell migration, which compromises local homeostasis and can trigger inflammatory diseases. Thus, accumulation of both MHC class II+CD11b+ cells and pathogenic CD4+ T cells at the ventral vessels of the L5 cord stimulate the excessive expression of chemokines in non-immune cells to trigger the EAE relapse.

Bottom Line: Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood.Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse.Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

ABSTRACT
Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.

No MeSH data available.


Related in: MedlinePlus