Palmitic acid promotes t-bet and gata-3 mRNA degradation in NKT cells via regulated IRE1a-dependent decay

Abstract

Abstract 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 cell. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-g 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 RNase. Moreover, PA increased the degradation rates of gata-3 and t-bet mRNA, which were restored by IRE1 inhibition, indicating that gata-3 and t-bet are cleaved via regulated IRE1a-dependent decay (RIDD). A PA-rich diet suppressed IL-4 and IFN-g production by iNKT cells in wildtype mice, thereby attenuating arthritis. This study demonstrates that a saturated LCFA induced RIDD-mediated t-bet and gata-3 mRNA degradation in iNKT cells, thereby suppressing cytokine production.