Dysregulated autotaxin expression by T cells in multiple sclerosis

Area of Science:

• Neuroimmunology
• Molecular Immunology

Background:

• Multiple sclerosis (MS) involves autoreactive T cells infiltrating the central nervous system (CNS).
• Autotaxin (ATX) is implicated in T cell migration and is elevated in active MS.
• Previous studies showed ATX inhibition reduces neurological deficits in a mouse model of MS.

Purpose of the Study:

• To investigate the regulation of ATX expression in T cells from MS patients.
• To identify molecular mechanisms driving ATX upregulation during T cell activation in MS.

Main Methods:

• Analysis of ATX and HuR expression in resting and activated immune cells from MS patients and healthy controls.
• Treatment of MS patient Th1 and Th17 cells with interleukin-23 (IL-23).
• Chromatin immunoprecipitation (ChIP) and re-ChIP assays to examine IL-23 signaling pathways.

Main Results:

• ATX expression is lower at rest but significantly increases upon activation in MS patient immune cells compared to controls.
• HuR, an ATX mRNA stabilizer, shows a similar expression pattern in MS patients.
• IL-23 induces prolonged ATX expression in MS patient Th1 and Th17 cells.
• IL-23 signaling may involve pSTAT3/pSTAT4 heterodimers to induce ATX expression.

Conclusions:

• Specific T cell subsets in MS patients exhibit unique ATX regulation patterns upon activation.
• IL-23 and the HuR protein are key regulators of sustained ATX expression in pathogenic T cells.
• These findings identify potential cellular sources and drivers of elevated serum ATX in MS.