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Defective T cell metabolism implicated in multiple sclerosis

Cell behaviour is largely governed by the regulation of metabolism. Defects in these processes could lead to autoimmune diseases such as multiple sclerosis.
Defective T cell metabolism implicated in multiple sclerosis
Accumulating evidence underscores the importance of cholesterol metabolism in immune responses. Perturbation of the steroid pathways modulates inflammation and potentially promotes autoimmune disease.

Cholesterol metabolites known as oxysterols may also be involved in the pathogenesis of multiple sclerosis, an autoimmune disease associated with nervous system demyelination and inflammatory infiltrates of lymphocytic and mononuclear cells.

The EU-funded OXYSTEROLS AND TR1 (Oxysterols and IL-27-induced Type 1 regulatory T cells in experimental autoimmune encephalomyelitis) project investigated how lipid metabolism affects the pathogenesis of autoimmune diseases. Their work focused on the enzyme cholesterol 25-hydroxylase (Ch25h) that metabolises cholesterol and its role during normal CD4+ T cell differentiation and in multiple sclerosis.

Scientists examined the levels of oxysterol-converting enzymes on various subsets of T helper CD4+ T cells activated in vitro. They encountered high levels of Ch25h during T cell differentiation by the cytokine interleukin-27. The products of cholesterol metabolism also suppressed the secretion of other cytokines, thereby contributing to a pro-inflammatory response. Mechanistic insight unveiled a role for Stat1 signalling, an important signalling pathway during inflammation.

In an experimental mouse model of autoimmune encephalomyelitis (EAE), the consortium discovered that the lack of Ch25h delayed EAE onset and reduced disease severity compared to wild-type mice. This supports a pro-inflammatory role for oxysterols during EAE.

Collectively, the findings of the OXYSTEROLS AND TR1 study highlight the regulatory role of the Ch25h pathway in immune responses. The dual role of Ch25h at inhibiting the generation of regulatory T cells and promoting the trafficking of pathogenic T cells during autoimmune disease identifies oxysterols as a potential therapeutic target.

Related information


Metabolism, multiple sclerosis, autoimmune disease, oxysterol, T cells, Ch25h
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