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The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis.

ABSTRACT: Multiple sclerosis (MS) is an autoimmune disease characterized by peripheral activation of CD4(+) T cells that migrate into the central nervous system (CNS) and mount an autoimmune neuroinflammatory attack on myelin and oligodendrocytes. Secondary to these events, however equally destructive, is the generation of inflammatory-mediated reactive oxygen and nitrogen species generated by persistently activated microglia and astrocytes. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that regulates genetic expression of many protective antioxidant and detoxication enzymes. Here we describe the Nrf2 modulation of innate and adaptive immune responses in an acute autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE). Wild-type (WT) mice and Nrf2 knockout mice were immunized with myelin oligodendrocyte glycoprotein (MOG 35-55) and monitored daily for clinical scores of disease. Disruption of Nrf2 resulted in a more severe clinical course, a more rapid onset, and a greater percentage of mice with the disease. Furthermore, increased immune cell infiltration and glial cell activation in spine was observed. In conjunction, we observed increased inflammatory enzyme (iNOS, phox-47, gp91-phox, and phox-67), cytokine (IFN-gamma, IL1-b, TNF-alpha, and IL-12), and chemokine (BLC and MIG) gene expression levels in the Nrf2-deficient mice compared to the WT mice, supporting the notion that Nrf2 can modulate an autoimmune neuroinflammatory response. Our results show that the absence of Nrf2 exacerbates the development of EAE and thus suggests that activation of Nrf2 may then attenuate pathogenesis of autoimmune diseases such as MS as well as other neurodegenerative diseases that present with neuroinflammation.

SUBMITTER: Johnson DA

PROVIDER: S-EPMC2902921 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundConstipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).MethodsConstipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood-brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups.ResultsCompared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood-brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota.ConclusionsOur results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

Project description: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 MOG35-55 immunization, 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.

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The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis.

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