Suppression of experimental autoimmune encephalomyelitis by extracellular adherence protein of Staphylococcus aureus
Changping Xie1, Pilar Alcaide, Brian V Geisbrecht
1Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Multiple sclerosis (MS) is a devastating inflammatory disorder of the central nervous system (CNS). A major hallmark of MS is the infiltration of T cells reactive against myelin components. T cell infiltration is mediated by the interaction of integrins of the beta1 and beta2 family expressed by lymphocytes with their endothelial counter-receptors, vascular cell adhesion molecule 1 and intercellular adhesion molecule (ICAM)-1, respectively. We have reported previously that extracellular adherence protein (Eap) of Staphylococcus aureus exerts antiinflammatory activities by interacting with ICAM-1 and blocking beta2-integrin-dependent neutrophil recruitment. Here, we report that Eap inhibits experimental autoimmune encephalomyelitis (EAE) in mice. In vitro, Eap reduced adhesion of peripheral blood T cells to immobilized ICAM-1 as well as their adhesion and transmigration of TNF-activated human endothelium under static and shear flow conditions. These inhibitory effects were corroborated in two mouse models of inflammation. In a delayed-type hypersensitivity model, both T cell infiltration and the corresponding tissue edema were significantly reduced by Eap. In addition, Eap administration prevented the development of EAE and markedly decreased infiltration of inflammatory cells into the CNS. Strikingly, intervention with Eap after the onset of EAE suppressed the disease. Collectively, our findings indicate that Eap represents an attractive treatment for autoimmune neuroinflammatory disorders such as MS.
Insights
Extracellular adherence protein (Eap) from Staphylococcus aureus reduces T cell infiltration in central nervous system inflammation. Eap effectively inhibits experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS).
Area of Science:
- Neuroimmunology
- Microbial immunology
- Inflammatory diseases
Background:
- Multiple sclerosis (MS) is a CNS inflammatory disorder characterized by T cell infiltration against myelin.
- T cell infiltration involves lymphocyte integrins interacting with endothelial counter-receptors like ICAM-1.
- Staphylococcus aureus extracellular adherence protein (Eap) previously showed anti-inflammatory effects by blocking neutrophil recruitment via ICAM-1.
Purpose of the Study:
- To investigate the efficacy of Eap in inhibiting experimental autoimmune encephalomyelitis (EAE), a mouse model for MS.
- To determine Eap's effects on T cell adhesion and transmigration across inflamed endothelium.
- To assess Eap's therapeutic potential for autoimmune neuroinflammatory disorders.
Main Methods:
- In vitro assays measuring T cell adhesion to ICAM-1 and transmigration across TNF-activated endothelium under static and flow conditions.
- In vivo studies using mouse models: delayed-type hypersensitivity and EAE.
- Administration of Eap before or after EAE onset to evaluate preventative and therapeutic effects.
Main Results:
- Eap significantly reduced peripheral blood T cell adhesion to ICAM-1 in vitro.
- Eap inhibited T cell adhesion and transmigration across inflamed human endothelium.
- Eap treatment decreased T cell infiltration and edema in a delayed-type hypersensitivity model.
- Eap administration prevented EAE development and reduced CNS inflammatory cell infiltration.
- Eap suppressed established EAE when administered after disease onset.
Conclusions:
- Eap demonstrates potent anti-inflammatory effects relevant to autoimmune neuroinflammation.
- Eap inhibits key T cell recruitment mechanisms implicated in MS pathogenesis.
- Eap shows promise as a therapeutic agent for multiple sclerosis and similar disorders.
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