An Increase in Tolerogenic Dendritic Cell and Natural Regulatory T Cell Numbers during Experimental Autoimmune Encephalomyelitis in <i>Rras</i>−/− Mice Results in Attenuated Disease

Ray, Avijit; Basu, Sreemanti; Miller, Nichole M.; Chan, Andrew M.; Dittel, Bonnie N.

doi:10.4049/jimmunol.1302254

Cited by 17 publications

(30 citation statements)

References 83 publications

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“…injection of 200 ng pertussis toxin (List Biological Laboratories, Campbell, CA) on days 0 and 2, as described (Ray et al 2014). EAE was induced in B10.PL mice by i.v.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Zhang

Ray

Miller

et al. 2015

Journal of Neurochemistry

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Oxidative stress is thought to contribute to disease pathogenesis in the central nervous system (CNS) disease multiple sclerosis (MS). Myeloperoxidase (MPO), a potent peroxidase that generates toxic radicals and oxidants, is increased in the CNS during MS. However, the exact mechanism whereby MPO drives MS pathology is not known. We addressed this question by inhibiting MPO in mice with experimental autoimmune encephalomyelitis (EAE) using our non-toxic MPO inhibitor KYC. We found that therapeutic administration of KYC for five days starting at the peak of disease significantly attenuated EAE disease severity, reduced myeloid cell numbers and permeability of the blood-brain-barrier (BBB). These data indicate that inhibition of MPO by KYC restores BBB integrity thereby limiting migration of myeloid cells into the CNS that drive EAE pathogenesis. In addition, these observations indicate that KYC may be an effective therapeutic agent for the treatment of MS.

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“…injection of 200 ng pertussis toxin (List Biological Laboratories, Campbell, CA) on days 0 and 2, as described (Ray et al 2014). EAE was induced in B10.PL mice by i.v.…”

Section: Methodsmentioning

confidence: 99%

“…Spinal cord sections (10 µm) were stained with anti-mouse CD11b-biotin and SMI-32 followed by staining with streptavidin Alexa 405 and goat anti-mouse Alexa-546, as described (Ray et al 2014). Isotype-matched antibodies were used as specificity controls.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Zhang

Ray

Miller

et al. 2015

Journal of Neurochemistry

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“…BrdU + B cells were tracked 1, 30, and 45 days after the last BrdU injection using the APC BrdU flow kit (BD Biosciences, San Diego, CA). For the B cell turnover assay, mice were provided with BrdU in the drinking water (0.8 mg/ml) for nine days, and the next day BrdU + B cells were detected using flow cytometry (33, 34). …”

Section: Methodsmentioning

confidence: 99%

Gut Microbial Dysbiosis Due to Helicobacter Drives an Increase in Marginal Zone B Cells in the Absence of IL-10 Signaling in Macrophages

Ray

Basu

Gharaibeh

et al. 2015

The Journal of Immunology

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It is clear that IL-10 plays an essential role in maintaining homeostasis in the gut in response to the microbiome. However, it is unknown whether IL-10 also facilitates immune homeostasis at distal sites. To address this question, we asked whether splenic immune populations were altered in IL-10-deficient (Il10−/−) mice in which differences in animal husbandry history were associated with susceptibility to spontaneous enterocolitis that is microbiome-dependent. The susceptible mice exhibited a significant increase in splenic macrophages, neutrophils and marginal zone (MZ) B cells that was inhibited by IL-10 signaling in myeloid, but not B cells. The increase in macrophages was due to increased proliferation that correlated with a subsequent enhancement in MZ B cell differentiation. Cohousing and antibiotic treatment studies suggested that the alteration in immune homeostasis in the spleen was microbiome-dependent. 16S rRNA sequencing revealed that susceptible mice harbored a different microbiome with a significant increase in the abundance of the bacterial genus Helicobacter. The introduction of H. hepaticus to the gut of nonsusceptible mice was sufficient to drive macrophage expansion and MZ B cell development. Given that myeloid cells and MZ B cells are part of the first line of defense against blood-borne-pathogens, their increase following a breach in the gut epithelial barrier would be protective. Thus IL-10 is an essential gatekeeper that maintains immune homeostasis at distal sites that can become functionally imbalanced upon the introduction of specific pathogenic bacteria to the intestinal track.

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“…The more complex studies used experimental autoimmune encephalomyelitis (EAE) animal models. In the EAE model, regulatory T cells and the cytokine interleukin‐10 (IL‐10), are two important negative regulators of disease development . Expansion of Th2 cells or inhibition of Th1/Th17 cells ameliorates EAE disease .…”

Section: Introductionmentioning

confidence: 99%

Inverse correlation of expression of microRNA‐140‐5p with progression of multiple sclerosis and differentiation of encephalitogenic T helper type 1 cells

et al. 2016

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Summary The role of microRNA in the regulation of encephalitogenic T‐cell development is of interest in understanding the pathogenesis of multiple sclerosis (MS). Direct binding of microRNAs to their target mRNAs usually suppresses gene expression and facilitates mRNA degradation. In this study, we observed that the expression of several microRNAs was significantly altered in patients with MS. Interestingly, the expression of miR‐140‐5p, among other microRNAs, was significantly decreased in the peripheral blood mononuclear cells of patients with MS, and this microRNA may regulate encephalitogenic T helper type 1 (Th1) cell differentiation. The expression level of miR‐140‐5p was inversely correlated with disease severity with greater reduction in relapsing disease compared with remitting disease. Transfection of synthetic miR‐140‐5p in peripheral blood mononuclear cells suppressed encephalitogenic Th1 differentiation. Signal transducer and activator of transcription 1 (STAT1) was the functional target of miR‐140‐5p – transfection of the synthetic miR‐140‐5p suppressed activation of STAT1 and the expression of its downstream target, T‐bet. Our results suggested that miR‐140‐5p is probably involved in the regulation of encephalitogenic T cells in the pathogenesis of MS.

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An Increase in Tolerogenic Dendritic Cell and Natural Regulatory T Cell Numbers during Experimental Autoimmune Encephalomyelitis in Rras−/− Mice Results in Attenuated Disease

Cited by 17 publications

References 83 publications

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Gut Microbial Dysbiosis Due to Helicobacter Drives an Increase in Marginal Zone B Cells in the Absence of IL-10 Signaling in Macrophages

Inverse correlation of expression of microRNA‐140‐5p with progression of multiple sclerosis and differentiation of encephalitogenic T helper type 1 cells

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