Superantigen overcomes resistance of IL-6-deficient mice towards MOG-induced EAE by a TNFR1 controlled pathway
H P Eugster1, K Frei, F Winkler
1Section of Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.
Abstract:
Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) leads to a chronic form of disease characterized by demyelination, inflammation and gliosis in the central nervous system (CNS). Recently IL-6 and LT alpha were found to be required for induction of the disease. The main features associated with EAE resistance of IL-6(-/-) and LT alpha(-/-) mice were reduced T cell proliferation and endothelial activation. As shown here treatment of MOG-immunized IL-6(-/-) mice with staphylococcal enterotoxin B (SEB)reversed their resistance to MOG-induced EAE. SEB failed to restore susceptibility to EAE in LT alpha(-/-) mice. The effect of SEB to induce EAE in IL-6(-/-) mice depends on TNF receptor type 1 (TNFR1) signaling because IL-6/TNF/LT alpha(-/-) and IL-6/TNFR1(-/-) are refractory to SEB. TNFR1 is involved in SEB induced trafficking of T cells into the CNS as evidenced by the failure to up-regulate VCAM-1 on CNS endothelium and lack of accumulation of V beta 8(+) T cells in the CNS of IL-6/TNFR1(-/-) mice upon immunization with MOG and treatment with SEB. The course of SEB triggered EAE in MOG immunized IL-6(-/-) mice was characterized by reduced severity and duration of clinical manifestations, which were associated with a significant drop of CNS infiltrating neutrophils and MIP-2 expression after peak disease. Taken collectively the effect of SEB to overcome EAE resistance points to a transient IL-6 independent but TNFR1 dependent proinflamatory pathway in EAE pathogenesis and suggests a crucial function for IL-6 in disease perpetuation.
Insights
Staphylococcal enterotoxin B (SEB) can overcome resistance to experimental autoimmune encephalomyelitis (EAE) in mice lacking interleukin-6 (IL-6). This effect requires TNF receptor type 1 (TNFR1) signaling and highlights a transient inflammatory pathway in EAE.
Area of Science:
- Neuroimmunology
- Autoimmune Diseases
- Central Nervous System Inflammation
Background:
- Experimental autoimmune encephalomyelitis (EAE) is a model for CNS inflammatory diseases.
- Interleukin-6 (IL-6) and Lymphotoxin alpha (LT alpha) are critical for EAE induction.
- Mice lacking IL-6 or LT alpha exhibit resistance to EAE due to reduced T cell proliferation and endothelial activation.
Purpose of the Study:
- To investigate the role of staphylococcal enterotoxin B (SEB) in overcoming EAE resistance in IL-6 deficient mice.
- To elucidate the signaling pathways involved in SEB-mediated EAE induction.
Main Methods:
- Induction of EAE in IL-6(-/-) and LT alpha(-/-) mice using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG).
- Treatment of MOG-immunized mice with SEB.
- Analysis of EAE susceptibility, T cell trafficking, and inflammatory markers in wild-type and knockout mice (IL-6(-/-), LT alpha(-/-), IL-6/TNFR1(-/-)).
Main Results:
- SEB treatment reversed EAE resistance in MOG-immunized IL-6(-/-) mice, but not in LT alpha(-/-) mice.
- SEB-induced EAE in IL-6(-/-) mice was dependent on TNF receptor type 1 (TNFR1) signaling.
- TNFR1 signaling was crucial for T cell trafficking into the CNS, evidenced by VCAM-1 expression and T cell accumulation.
- SEB-triggered EAE in IL-6(-/-) mice showed reduced severity and duration, with decreased neutrophil infiltration and MIP-2 expression.
Conclusions:
- SEB can overcome IL-6-independent resistance to MOG-induced EAE via a TNFR1-dependent pathway.
- This suggests a transient pro-inflammatory pathway in EAE pathogenesis.
- IL-6 plays a crucial role in the perpetuation of EAE, while TNFR1 is involved in initiating T cell trafficking into the CNS.
