Dihydroartemisinin Shows Promising Effects in the Treatment of Experimental Autoimmune Encephalomyelitis and Maintains Inflammatory Homeostasis by Targeting AXL in Microglia

2020 ◽  
Author(s):  
Zhu Xiaoxin ◽  
Ran Qingsen ◽  
Qi Li ◽  
Liu Li ◽  
Sun Lidong ◽  
...  
Keyword(s):  
Gait Analysis ◽  
Autoimmune Encephalomyelitis ◽  
Disease Treatment ◽  
Immunological Responses ◽  
Clinical Scores ◽  
Immune Balance ◽  
Bv2 Cells ◽  
Well Assay ◽  
Treg Differentiation

Abstract Background: During EAE progression, the endogenous mechanisms mediating nervous autoimmune inflammation balance, as represented by AXL, were proved to be pathologically disturbed, immune balance and axon repair. Therapeutically, by activating AXL signaling, the inflammatory rebalance from promotion to resolution has attracted increasing attention and showed advantages in autoimmune disease treatment. Previous studies implied that DHA had potential effects in treating autoimmune diseases. However, the detailed mechanisms in inflammation regulation, especially in CNS, remain unclear.Methods: C57BL/6 mice were immunized with MOG35-55 and treated daily with DHA. Then clinical scores, pathology, and ethology features of EAE were assessed through histological staining (H&E, LFB staining), TEM and gait analysis. Moreover, DHA-responsive cells and genes were screened by 10x Genomics. The immunological responses to DHA were measured by flow cytometry and fluorescence microscope in BV2 cells. The concentrations and bio-activities of chemokines were respectively evaluated through ELISA and trans-well assay. Results: After DHA treatment, the clinical scores and body weight were significantly improved. Histologically, mice showed slighter spinal cord lesion, less inflammatory cuffs. By using gait analysis, DHA obviously improved physical coordination. 10x Genomics demonstrated that DHA selectively upregulated AXL expression in microglia. Immunologically, by enhancing AXL signaling, the phagocytic and chemotactic potential of microglia and the Treg differentiation followed by upregulating PDL1 were significantly influenced by DHA. Conversely, specific blocking of AXL by SGI7079 was sufficient to reverse above-mentioned functions. Molecularly, DHA specifically rebalanced the overactivated inflammation through STAT1:SOCS3: AXL: IFNAR pathway. Conclusions: The present study highlighted the central role of AXL signaling in DHA mediated inflammatory transition.

scholarly journals B cell-mediated immunomodulation by S-nitrosoglutathione (GSNO) in experimental autoimmune encephalomyelitis

2020 ◽  
Author(s):  
Judong Kim ◽  
S.M. Touhidul Islam ◽  
Jeseong Won ◽  
Avtar K. Singh ◽  
Inderjit Singh
Keyword(s):  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
B Cell ◽  
Cell Function ◽  
Autoimmune Encephalomyelitis ◽  
Immune Balance ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model for human multiple sclerosis (MS), a demyelinating autoimmune disease mediated by T and B lymphocytes. The aim of the present study was to investigate the role of S-nitrosoglutathione (GSNO), a physiological nitric oxide carrier molecule, in regulation of effector or regulatory B cell function as IL-6 and IL-10 expressions and thus the potential role of GSNO in targeting B cell-mediated immunopathogenesis in MS using EAE model. Methods To this purpose, the in vivo EAE mouse model, generated by immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, or in vitro model of cultured B cells stimulated with lipopolysaccharide or anti-IgM antibody were treated with exogenous GSNO or N6022, an inhibitor of GSNO reductase (GSNOR; GSNO degrading enzyme) to increase endogenous GSNO, and then analyzed for B cell specific IL-6 and IL-10 expression. Results In EAE model, administration of exogenous GSNO or inhibition of endogenous GSNO catabolism by N6022 treatment ameliorated the clinical disease with decreased CNS infiltration of B cells. In addition, GSNO/N6022 treatments increased the number of IL-10+ B cells but decreased the number of IL-6+ B cells in the CNS and spleen. Accordingly, GSNO/N6022 treatments increased the expression of IL-10 while reducing the IL-6 expression in the blood. Similar observations were also made in in vitro B cell culture model where GSNO treatment increased the IL-10+ B cells but decreased the IL-6+ B cells under BCR or TLR4 stimulatory conditions and under CD40 and BAFF co-stimulatory conditions. Accordingly, GSNO treatment increased the B cell production of IL-10 but reduced the IL-6 production under both stimulatory and co-stimulatory conditions. In vitro stimulation and co-stimulation of cultured naïve B cells increased two major distinct B cell populations; CD1dlow CD5high and CD1dhigh CD5high. In both populations, GSNO treatment increased the number of IL-10+ cells but decreased the IL-6+ cells. Conclusion These data document, for the first time, that cellular GSNO homeostasis is a critical target for the regulation of IL-10+ B cells vs. IL-6+ B cells mediated immune balance under auto-immune disease conditions.

scholarly journals Neuronutraceuticals Modulate Lipopolysaccharide- or Amyloid-β 1-42 Peptide-Induced Transglutaminase 2 Overexpression as a Marker of Neuroinflammation in Mouse Microglial Cells

2021 ◽  
Vol 11 (12) ◽  
pp. 5718
Author(s):  
Nicola Gaetano Gatta ◽  
Andrea Parente ◽  
Francesca Guida ◽  
Sabatino Maione ◽  
Vittorio Gentile
Keyword(s):  
Microglial Cell ◽  
Amyloid Β ◽  
Transglutaminase 2 ◽  
Microglial Cells ◽  
Tissue Type ◽  
Microglial Cell Line ◽  
Bv2 Cells ◽  
Important Marker

Background: Tissue type 2 transglutaminase (TG2, E.C. 2.3.2,13) is reported to be involved in the phagocytosis of apoptotic cells in mouse microglial BV2 cells and peripheral macrophages. In this study, by using lipopolysaccharide (LPS)- or amyloid-β 1-42 (Aβ 1-42) peptide-stimulated microglial cell line BV2 and mouse primary microglial cells, we examined the effects of different neuronutraceutical compounds, such as curcumin (Cu) and N-Palmitoylethanolamine (PEA), known for their anti-inflammatory activity, on TG2 and several inflammatory or neuroprotective biomarker expressions. Methods: Mouse BV2 cells were treated with LPS or Aβ1-42 in the presence of curcumin or PEA, in order to evaluate the expression of TG2 and other inflammatory or neuroprotective markers using Real Time-PCR and Western blot analyses. Results: Curcumin and PEA were capable of reducing TG2 expression in mouse microglial cells during co-treatment with LPS or Aβ 1-42. Conclusions: The results show the role of TG2 as an important marker of neuroinflammation and suggest a possible use of curcumin and PEA in order to reduce LPS- or Aβ1-42-induced TG2 overexpression in mouse microglial cells.

scholarly journals Circulating Tfh cell and subsets distribution are associated with low‐responsiveness to hepatitis B vaccination

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Mingjuan Yin ◽  
Yongzhen Xiong ◽  
Dongmei Liang ◽  
Hao Tang ◽  
Qian Hong ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Hepatitis B Vaccine ◽  
Hepatitis B Vaccination ◽  
Cellular Mechanisms ◽  
Immunological Responses ◽  
Follicular Helper ◽  
Low Responders ◽  
Specific Subset ◽  
Antibody Titers

Abstract Background An estimated 5–10 % of healthy vaccinees lack adequate antibody response following receipt of a standard three-dose hepatitis B vaccination regimen. The cellular mechanisms responsible for poor immunological responses to hepatitis B vaccine have not been fully elucidated to date. Methods There were 61 low responders and 56 hyper responders involved in our study. Peripheral blood samples were mainly collected at D7, D14 and D28 after revaccinated with a further dose of 20 µg of recombinant hepatitis B vaccine. Results We found low responders to the hepatitis B vaccine presented lower frequencies of circulating follicular helper T (cTfh) cells, plasmablasts and a profound skewing away from cTfh2 and cTfh17 cells both toward cTfh1 cells. Importantly, the skewing of Tfh cell subsets correlated with IL-21 and protective antibody titers. Based on the key role of microRNAs involved in Tfh cell differentiation, we revealed miR-19b-1 and miR-92a-1 correlated with the cTfh cell subsets distribution and antibody production. Conclusions Our findings highlighted a decrease in cTfh cells and specific subset skewing contribute to reduced antibody responses in low responders.

The Role of Gait Analysis in Clinical Medicine: A Survey of UK Centres

1987 ◽  
Vol 16 (4) ◽  
pp. 221-227 ◽  
Author(s):  
N Messenger ◽  
P Bowker
Keyword(s):  
Gait Analysis ◽  
Clinical Medicine ◽  
Final Analysis ◽  
Clinical Work ◽  
Clinical Context ◽  
Clinical Value ◽  
Analysis Techniques ◽  
Subjective Views ◽  
The Uk

This paper reports the results of a survey carried out to assess the clinical usage currently being made of gait analysis facilities within the UK. Thirty-five centres were circulated with a questionnaire which requested information under four main headings: (i) equipment, (ii) research projects, (iii) clinical service commitments, and (iv) subjective views of the ultimate clinical value of the service. Of the 25 completed questionnaires returned, 16 were suitable for inclusion in the final analysis of data. The survey provided useful data on the equipment and facilities available in each centre together with details of the service available to prospective referring clinicians. Ten centres were considered as being currently involved in some clinical work, with six of these being routinely involved. The respondents generally felt that gait analysis techniques have a clinical context, if not yet routinely, but the numbers of referrals to the centres is still quite small. A number of areas worthy of further work were identified by the respondents. It is hoped that presentation of these results will stimulate dialogue between centres and between clinicians and bioengineers.

scholarly journals Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Ning Qu ◽  
Mingli Xu ◽  
Izuru Mizoguchi ◽  
Jun-ichi Furusawa ◽  
Kotaro Kaneko ◽  
...  
Keyword(s):  
Th17 Cell ◽  
Th17 Cells ◽  
Functional Role ◽  
Inflammatory Diseases ◽  
Interleukin 17 ◽  
T Helper ◽  
T Helper 17 ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

T-helper 17 (Th17) cells are characterized by producing interleukin-17 (IL-17, also called IL-17A), IL-17F, IL-21, and IL-22 and potentially TNF-α and IL-6 upon certain stimulation. IL-23, which promotes Th17 cell development, as well as IL-17 and IL-22 produced by the Th17 cells plays essential roles in various inflammatory diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, colitis, and Concanavalin A-induced hepatitis. In this review, we summarize the characteristics of the functional role of Th17 cells, with particular focus on the Th17 cell-related cytokines such as IL-17, IL-22, and IL-23, in mouse models and human inflammatory diseases.

scholarly journals Endothelial Microsomal Prostaglandin E Synthetase-1 Upregulates Vascularity and Endothelial Interleukin-1β in Deteriorative Progression of Experimental Autoimmune Encephalomyelitis

2018 ◽  
Vol 19 (11) ◽  
pp. 3647 ◽  
Author(s):  
Takako Takemiya ◽  
Marumi Kawakami ◽  
Chisen Takeuchi
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Vascular Endothelial Cells ◽  
Immunohistochemical Analysis ◽  
Interleukin 1Β ◽  
Prostaglandin E ◽  
Vascular Endothelial ◽  
Autoimmune Encephalomyelitis ◽  
Ep Receptor ◽  
Experimental Autoimmune

Microsomal prostaglandin E synthetase-1 (mPGES-1) is an inducible terminal enzyme for the production of prostaglandin E2 (PGE2). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, mPGES-1 is induced in vascular endothelial cells (VECs) around inflammatory foci and facilitates inflammation, demyelination, and paralysis. Therefore, we investigated the role of CD31-positive VECs in mPGES-1-mediated EAE aggravation using immunohistochemical analysis and imaging of wild-type (wt) and mPGES-1-deficient (mPGES-1−/−) mice. We demonstrated that EAE induction facilitated vascularity in inflammatory lesions in the spinal cord, and this was significantly higher in wt mice than in mPGES-1−/− mice. In addition, endothelial interleukin-1β (IL-1β) production was significantly higher in wt mice than in mPGES-1−/− mice. Moreover, endothelial PGE2 receptors (E-prostanoid (EP) receptors EP1–4) were expressed after EAE induction, and IL-1β was induced in EP receptor-positive VECs. Furthermore, IL-1 receptor 1 expression on VECs was increased upon EAE induction. Thus, increased vascularity is one mechanism involved in EAE aggravation induced by mPGES-1. Furthermore, mPGES-1 facilitated the autocrine function of VECs upon EP receptor induction and IL-1β production, modulating mPGES-1 induction in EAE.

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