Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway
| العنوان: | Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway |
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| المؤلفون: | Chuanzhu Yan, Tong Du, Ruonan Duan, Wenjie Sun, Jiangxia Li, Ai Liu, Qiji Liu, Anran Wang, Xi Li, Chun-Lin Yang |
| المصدر: | Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-17 (2021) Journal of Neuroinflammation |
| بيانات النشر: | BMC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Central Nervous System, Indoleamine 2,3-dioxygenase, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Immunology, Inflammation, Proinflammatory cytokine, Myelin oligodendrocyte glycoprotein, Suppressor of MEK1, Interleukin 1β, Gene Knockout Techniques, Interferon-gamma, Mice, Cellular and Molecular Neuroscience, Immune system, Phosphoprotein Phosphatases, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Medicine, Myeloid Cells, RC346-429, Neuroinflammation, Experimental autoimmune encephalomyelitis, biology, Microglia, business.industry, Research, General Neuroscience, Multiple sclerosis, medicine.disease, Peptide Fragments, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Receptors, Aryl Hydrocarbon, Neurology, biology.protein, Cytokines, Myelin-Oligodendrocyte Glycoprotein, Neurology. Diseases of the nervous system, medicine.symptom, business, Spleen, Signal Transduction |
| الوصف: | BackgroundExperimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE.MethodsC57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis.ResultsHere, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1-/+mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+EAE mice.ConclusionsThe present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination. |
| اللغة: | English |
| تدمد: | 1742-2094 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::215c9b20f7ee7145b6e581012c1bf596Test https://doaj.org/article/c9193ccafe52499aaf1c33b9a71e189aTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....215c9b20f7ee7145b6e581012c1bf596 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17422094 |
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