Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function.

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Pathogenic T helper 17 (Th17) cells are implicated in autoimmune and inflammatory diseases.
• Th17 cell function is regulated by T cell receptor (TCR) signaling and STAT3 activation.
• TCR engagement triggers STIM1 activation and calcium influx via CRAC channels.

Purpose of the Study:

• To investigate the role of STIM1 and calcium influx in pathogenic Th17 cell function.
• To determine the impact of STIM1/calcium signaling on STAT3-driven inflammation.
• To elucidate the link between calcium influx, mitochondrial function, and Th17 pathogenicity.

Main Methods:

• Utilized a mouse model with hyperactive STAT3 (STAT3C) in Th17 cells.
• Deleted STIM1 in pathogenic Th17 cells.
• Assessed Th17 cell function, gene expression, mitochondrial function, oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production.
• Analyzed inflammatory markers in vivo.

Main Results:

• Abolishing STIM1 and calcium influx in STAT3C-expressing Th17 cells attenuated pathogenicity and inflammation.
• STIM1 deletion in Th17 cells reduced mitochondrial function and OXPHOS gene expression.
• STIM1 deletion enhanced ROS production and promoted a non-pathogenic Th17 gene signature, impairing Th17 cell function.

Conclusions:

• Calcium influx is a critical regulator of mitochondrial function in pathogenic Th17 cells.
• STIM1-mediated calcium influx is essential for maintaining the pathogenic function of Th17 cells.
• Targeting STIM1 and calcium influx pathways may offer therapeutic strategies for Th17-mediated inflammatory diseases.