Palmitate inhibits arthritis by inducing t-bet and gata-3 mRNA degradation in iNKT cells via IRE1α-dependent decay

Long chain fatty acids (LCFAs) exert pro-inflammatory effects in vivo. However, little is known regarding the effect of LCFAs on invariant (i) NKT cell functions. Here, we report an inhibitory effect of saturated LCFAs on transcription factors in iNKT cells. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-gamma production and reduced gata-3 and t-bet transcript levels in iNKT cells during TCR-mediated activation. In iNKT cells, PA was localized and induced dilation in the endoplasmic reticulum and increased the mRNA levels of downstream molecules of IRE1 alpha RNase. Moreover, PA increased the degradation rates of gata-3 and t-bet mRNA, which was restored by IRE1 alpha inhibition or transfection with mutant gata-3 or t-bet, indicating that gata-3 and t-bet are cleaved via regulated IRE1 alpha-dependent decay (RIDD). A PA-rich diet and PA injection suppressed IL-4 and IFN-gamma production by iNKT cells in C57BL/6, but not J alpha 18 knockout mice, which was restored by injection of STF083010, an IRE1 alpha-specific inhibitor. Furthermore, a PA-rich diet and PA injection attenuated arthritis in an iNKT cell-dependent manner. Taken together, our experiments demonstrate that a saturated LCFA induced RIDD-mediated t-bet and gata-3 mRNA degradation in iNKT cells, thereby suppressing arthritis.