Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling
Pernille M Madsen1, Haritha L Desu2, Juan Pablo de Rivero Vaccari3
1The Miami Project to Cure Paralysis, Dept. Neurological Surgery, University of Miami Miller School of Medicine, FL 33136, USA; Dept. Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Abstract:
The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in oligodendrocytes in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.
Insights
Oligodendroglial TNFR2 plays a protective role in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. Its absence accelerates disease onset and severity by promoting inflammation and immune cell infiltration in the central nervous system.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Tumor necrosis factor (TNF) is a pleiotropic cytokine implicated in multiple sclerosis (MS) pathogenesis.
- Distinct TNF forms signal through different receptors: membrane-bound TNF (tmTNF) via TNFR2, and soluble TNF (solTNF) via TNFR1.
- While solTNF/TNFR1 signaling is generally pro-inflammatory in MS models, tmTNF/TNFR2 signaling can be protective.
Purpose of the Study:
- To investigate the specific role of TNFR2 expressed in oligodendrocytes during the early stages of experimental autoimmune encephalomyelitis (EAE).
- To determine how oligodendroglial TNFR2 influences neuroinflammation and disease progression in an MS model.
Main Methods:
- Utilized a mouse model of EAE to study the early pathogenesis of MS.
- Generated mice with specific ablation of TNFR2 in oligodendrocytes.
- Assessed motor function, immune cell infiltration, microglial activation, blood-brain barrier permeability, and gene/cytokine expression post-EAE induction.
- Performed gene expression profiling on sorted oligodendrocytes.
Main Results:
- Mice lacking oligodendroglial TNFR2 exhibited an earlier onset and higher peak of motor dysfunction during EAE.
- Accelerated immune cell infiltration into the central nervous system was observed as early as 10 days post-induction in these mice.
- Lack of oligodendroglial TNFR2 led to increased microglial activation, blood-brain barrier permeability, and accelerated expression of inflammatory cytokines and inflammasome components.
- Gene expression profiling revealed robust upregulation of inflammatory genes in oligodendrocytes, with some elevated in TNFR2-deficient cells.
Conclusions:
- Oligodendrocytes are directly involved in modulating neuroinflammation and immune responses within the central nervous system during disease.
- Oligodendroglial TNFR2 signaling is a critical regulator of neuroinflammation and disease severity in EAE, demonstrating a protective role.
- Targeting oligodendroglial TNFR2 may offer a therapeutic strategy for managing inflammatory processes in multiple sclerosis.
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