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Autotaxin in encephalitogenic CD4 T cells as a therapeutic target for multiple sclerosis
Cora L Petersen-Cherubini1,2, Shawn P Murphy2, Matthew Xin2
1Neuroscience Graduate Program, The Ohio State University, Columbus, Ohio, USA.
Abstract:
Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the CNS. A defining characteristic of MS is the ability of autoreactive T lymphocytes to cross the blood-brain barrier and mediate inflammation within the CNS. Previous work from our lab found the gene Enpp2 to be highly upregulated in murine encephalitogenic T cells. Enpp2 encodes for the protein autotaxin, a secreted glycoprotein that catalyzes the production of lysophosphatidic acid and promotes transendothelial migration of T cells from the bloodstream into the lymphatic system. The present study sought to characterize autotaxin expression in T cells during CNS autoimmune disease and determine its potential therapeutic value. Myelin-activated CD4 T cells upregulated expression of autotaxin in vitro, and ex vivo analysis of CNS-infiltrating CD4 T cells showed significantly higher autotaxin expression compared with cells from healthy mice. In addition, inhibiting autotaxin in myelin-specific T cells reduced their encephalitogenicity in adoptive transfer studies and decreased in vitro cell motility. Importantly, using two mouse models of MS, treatment with an autotaxin inhibitor ameliorated EAE severity, decreased the number of CNS infiltrating T and B cells, and suppressed relapses, suggesting autotaxin may be a promising therapeutic target in the treatment of MS.
Insights
Autotaxin (Enpp2) is upregulated in T cells during central nervous system (CNS) autoimmune disease. Inhibiting autotaxin reduces T cell migration and disease severity, suggesting it as a potential therapeutic target for multiple sclerosis (MS).
Area of Science:
- Neuroimmunology
- Molecular Immunology
- Cell Biology
Background:
- Multiple sclerosis (MS) is a CNS autoimmune disease characterized by T lymphocyte infiltration across the blood-brain barrier.
- The gene Enpp2, encoding autotaxin, was previously found upregulated in encephalitogenic T cells.
- Autotaxin facilitates T cell transendothelial migration into lymphatic vessels.
Purpose of the Study:
- To investigate autotaxin expression in T cells during CNS autoimmune disease.
- To evaluate the therapeutic potential of targeting autotaxin in MS models.
Main Methods:
- Analysis of autotaxin expression in myelin-activated CD4 T cells in vitro and ex vivo.
- Assessment of autotaxin inhibition effects on T cell encephalitogenicity and motility.
- Treatment of mouse models of MS with an autotaxin inhibitor.
Main Results:
- Autotaxin expression was significantly higher in CNS-infiltrating CD4 T cells from diseased mice compared to healthy controls.
- Inhibition of autotaxin reduced T cell encephalitogenicity and in vitro motility.
- Autotaxin inhibitor treatment ameliorated experimental autoimmune encephalomyelitis (EAE) severity, reduced CNS immune cell infiltration, and suppressed relapses.
Conclusions:
- Autotaxin is upregulated in T cells during CNS autoimmune disease.
- Autotaxin inhibition demonstrates therapeutic potential for MS by reducing T cell migration and disease activity.
- Autotaxin represents a promising therapeutic target for multiple sclerosis treatment.
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