Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune
Han Gao1, Matt C Danzi2, Claire S Choi3
1The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Abstract:
In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here, we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.
Insights
Tumor necrosis factor receptor 2 (TNFR2) has opposing roles in microglia and monocytes/macrophages in multiple sclerosis models. Microglial TNFR2 protects against disease, while monocyte/macrophage TNFR2 promotes neuroinflammation.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Immunology
Background:
- Soluble tumor necrosis factor (TNF) exacerbates multiple sclerosis (MS) via TNF receptor 1 (TNFR1).
- Transmembrane TNF offers benefits through TNF receptor 2 (TNFR2) activation.
- The specific roles of TNFR2 in different myeloid cell populations during MS pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the distinct functions of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), an MS model.
- To elucidate the cell-specific impact of TNFR2 signaling on neuroinflammation and disease progression.
Main Methods:
- Utilized cell-specific gene targeting in a mouse model of EAE.
- Examined the effects of TNFR2 ablation in microglia and monocytes/macrophages on disease onset, severity, and immune cell infiltration in the central nervous system (CNS).
Main Results:
- TNFR2 deletion in microglia accelerated EAE onset, increasing leukocyte infiltration, T cell activation, and CNS demyelination.
- TNFR2 deletion in monocytes/macrophages suppressed EAE, reducing peripheral T cell activation and CNS immune cell infiltration and demyelination.
- Demonstrated a functional dichotomy for TNFR2 in myeloid cells.
Conclusions:
- Microglial TNFR2 signaling provides protective effects, limiting disease severity in EAE.
- Monocyte/macrophage TNFR2 signaling drives immune activation and initiates EAE.
- Targeting TNFR2 for neuroinflammatory diseases requires consideration of its opposing roles in distinct myeloid cell types.
