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Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway.
- Source :
-
Journal of neuroinflammation [J Neuroinflammation] 2021 Jun 28; Vol. 18 (1), pp. 145. Date of Electronic Publication: 2021 Jun 28. - Publication Year :
- 2021
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Abstract
- Background: Experimental 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.<br />Methods: C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG <subscript>35-55</subscript> ) 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.<br />Results: Here, 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 MOG <subscript>35-55</subscript> immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1 <superscript>-/+</superscript> 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 <superscript>-/+</superscript> EAE mice.<br />Conclusions: The 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.
- Subjects :
- Animals
Central Nervous System immunology
Central Nervous System physiopathology
Cytokines
Disease Models, Animal
Gene Knockout Techniques
Inflammation metabolism
Mice
Mice, Inbred C57BL
Microglia metabolism
Multiple Sclerosis immunology
Myelin-Oligodendrocyte Glycoprotein immunology
Myeloid Cells immunology
Myeloid Cells metabolism
Peptide Fragments immunology
Phosphoprotein Phosphatases metabolism
Signal Transduction
Spleen pathology
Central Nervous System pathology
Encephalomyelitis, Autoimmune, Experimental immunology
Encephalomyelitis, Autoimmune, Experimental metabolism
Encephalomyelitis, Autoimmune, Experimental pathology
Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism
Interferon-gamma metabolism
Microglia immunology
Phosphoprotein Phosphatases immunology
Receptors, Aryl Hydrocarbon metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1742-2094
- Volume :
- 18
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of neuroinflammation
- Publication Type :
- Academic Journal
- Accession number :
- 34183017
- Full Text :
- https://doi.org/10.1186/s12974-021-02193-0