Knockout of P2Y 12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells

Zhang, Jiang; Li, Zhenlong; Hu, Xuefei; Su, Qiong; He, Cong; Jing, Liu; Ren, Hua; Qian, Min; Liu, Junling; Cui, Shufang; Jiang, Wenzheng

doi:10.1016/j.bbi.2016.12.001

Cited by 25 publications

(27 citation statements)

References 52 publications

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“…EAE model was induced as previously described [ 41 ]. Briefly, Female mice at 8-10 wk of age were immunized subcutaneously in the flanks with 200 μg of MOG 35-55 peptides (purity >98%, GL Biochem Ltd., Shanghai) which were emulsified in complete Freund’s adjuvant (CFA) containing 500 μg of Mycobacterium tuberculosis H37RA (Difco Laboratories, USA).…”

Section: Methodsmentioning

confidence: 99%

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

Shi

Chen

et al. 2017

Oncotarget

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Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Previous study demonstrated histamine H3 receptor (H3R) was an important factor in pathophysiology of EAE and immethridine was the most selective agonist of H3R. However, whether immethridine has therapeutic effect on EAE and its mechanism remained to be defined. Here we constructed EAE mouse model by immunization of MOG35-55 peptides with complete Freund’s adjuvant, immethridine was used to treat EAE and its therapeutic effect was evaluated. The results showed that the treatment of immethridine could alleviate EAE. The percentage of Th1 and Th17 in the spleen from the treated EAE mice decreased and the surface molecules such as CD40, CD86 or MHCII on dendritic cells (DCs) were also down-regulated. To understand the effect of immethridine on DCs, bone marrow-derived DCs were prepared and the immunological functions were analyzed. The data demonstrated that immethridine could change the expression profiles of cytokines in DCs and inhibit the expression of the co-stimulatory molecules such as CD40 and CD86. Furthermore, immethridine also inhibited the antigen-presenting function of DCs and T cell differentiation induced by DCs. Signaling pathway analysis demonstrated that the phosphorylation of NF-κB p65 but not ERK1/2 in DCs was inhibited after the treatment of immethridine. These data strongly suggested that immethridine could inhibit the function of DCs and indicated the therapeutic potential on EAE.

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Section: Methodsmentioning

confidence: 99%

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

Shi

Chen

et al. 2017

Oncotarget

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“…In the past years, it drew extensive attention mainly for its importance in regulating the aggregation of blood platelet . Recently, there are several studies disclosed its potential on the progression of neurological diseases, such as multiple sclerosis and neuropathic pain, by modulating the function of dendritic cells and microglial cells. Latest reports suggest that microglial cells are actively engaged in the regulation of emotional behavior .…”

Section: Introductionmentioning

confidence: 99%

P2Y₁₂ deficiency in mouse impairs noradrenergic system in brain, and alters anxiety‐like neurobehavior and memory

Zheng

Zhou

Cao

et al. 2018

Genes Brain and Behavior

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Purinergic receptor P2Y (P2Y ), a G protein-coupled purinergic receptor, is widely distributed in nervous system and involved in the progression of neurological diseases such as multiple sclerosis and neuropathic pain. The central noradrenergic system actively participates in a number of neurophysiological processes. Nevertheless, whether there is any direct relevance between P2Y and noradrenergic signal transduction remains unknown. In the present study, we tested the hypothesis that lack of P2Y impaired noradrenergic signal transduction in mouse brain. Our results showed that P2Y knockout (KO) mice exhibited increased anxiety-like behavior in the open-field test (OFT) and elevated plus maze test and displayed deficits in memory in the radial-arm maze test (RAMT) and Morris water maze test (MWMT). They also exhibited reduced locomotion in the OFT and MWMT. Moreover, loss of P2Y decreased the level of noradrenaline and the expression of noradrenergic α receptors, subtypes α2 (ARα2b) in mouse cerebellum and hippocampus. Meanwhile, it hampered the protein kinase A (PKA)/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway in these brain regions. Taken together, our results showed for the first time that P2Y KO altered the anxiety, memory and locomotion of mice, which was closely associated with abnormal state of noradrenergic system in the brain. The findings implicate that P2Y plays an indispensable role in noradrenergic signal transduction; its deficit is insufficient to limit anxiety responses or supports cognitive performance and activity.

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Section: P2y Receptorsmentioning

confidence: 99%

“…To determine the effect of P2Y12 receptor in MS, knockout models of this receptor resulted in an enhanced EAE phenotype in mice (Zhang et al, 2017). The EAE pathology was characterized by an increase in IL-17A cytokine levels in serum, higher number of T-helper cell subset (Th17) in spleen and CNS, as well as the presence of granulocyte-macrophage colonystimulating factor (Zhang et al, 2017). Bone marrow-derived dendritic cells from P2Y12 −/− mice challenged to model EAE have increased release of IL-23, which is an essential factor to promote differentiation of CD4+ T cells toward the Th17 cell subtype (Zhang et al, 2017).…”

Section: P2y Receptorsmentioning

confidence: 99%

“…The EAE pathology was characterized by an increase in IL-17A cytokine levels in serum, higher number of T-helper cell subset (Th17) in spleen and CNS, as well as the presence of granulocyte-macrophage colonystimulating factor (Zhang et al, 2017). Bone marrow-derived dendritic cells from P2Y12 −/− mice challenged to model EAE have increased release of IL-23, which is an essential factor to promote differentiation of CD4+ T cells toward the Th17 cell subtype (Zhang et al, 2017). The authors concluded that P2Y12 receptors are important for balancing Th-cell populations, and receptor function dysregulation leads to altered cytokine profiles, contributing to EAE.…”

Section: P2y Receptorsmentioning

confidence: 99%

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Papel do receptor B2 de cininas na terapia da neurodegeneração dopaminérgica em modelo animal

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Knockout of P2Y 12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells

Cited by 25 publications

References 52 publications

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

P2Y₁₂ deficiency in mouse impairs noradrenergic system in brain, and alters anxiety‐like neurobehavior and memory

Papel do receptor B2 de cininas na terapia da neurodegeneração dopaminérgica em modelo animal

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Knockout of P2Y 12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells

Cited by 25 publications

References 52 publications

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

P2Y12 deficiency in mouse impairs noradrenergic system in brain, and alters anxiety‐like neurobehavior and memory

Papel do receptor B2 de cininas na terapia da neurodegeneração dopaminérgica em modelo animal

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P2Y₁₂ deficiency in mouse impairs noradrenergic system in brain, and alters anxiety‐like neurobehavior and memory