Palmitate inhibits arthritis by inducing t-bet and gata-3 mRNA degradation in iNKT cells via IRE1\u03b1-dependent decay

Jae Moon Koh,Doo Hyun Chung,Jae Sung Ko,Hye Young Kim,Yoon Kyung Jeon,Jae-Seon So

doi:10.1038/s41598-017-14780-4

Jae Moon Koh, Doo Hyun Chung + Show 4 more

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https://doi.org/10.1038/s41598-017-14780-4

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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 cells. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-γ 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 IRE1α RNase. Moreover, PA increased the degradation rates of gata-3 and t-bet mRNA, which was restored by IRE1α inhibition or transfection with mutant gata-3 or t-bet, indicating that gata-3 and t-bet are cleaved via regulated IRE1α-dependent decay (RIDD). A PA-rich diet and PA injection suppressed IL-4 and IFN-γ production by iNKT cells in C57BL/6, but not Jα18 knockout mice, which was restored by injection of STF083010, an IRE1α-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.

Highlights

Several studies have reported that Long chain fatty acids (LCFAs) affect various immune cell functions
To investigate whether saturated and unsaturated LCFAs regulate the function of Invariant natural killer T (iNKT) cells, we treated mouse iNKT cell line with various saturated and unsaturated LCFAs in the presence of anti-CD3 and CD28 monoclonal antibodies or α-GalCer-loaded bone marrow-derived dendritic cells (BMDCs)
Consistent with these iNKT cell line experiments, the palmitic acid-induced inhibition of IL-4 and IFN-γ production and reductions in t-bet and gata-3 mRNA expression levels were found in CD1d/α-GalCer+ iNKT cells sorted from liver mononuclear cells of C57BL/6 mice (Fig. 1d)

Summary

Introduction

Several studies have reported that LCFAs affect various immune cell functions. O’Sullivan et al demonstrated that de novo fatty acid synthesis was indispensable for the Th17 and regulatory T cell differentiation of CD4+ T cells, as well as the survival of CD8+ T cells[3,4], indicating that intracellular fatty acid synthesis modulates certain functions of conventional CD4+ and CD8+ T cells. Among the exogenous LCFAs, palmitic acid upregulated the secretion of IL-1β and IL-18 via NLRP3 inflammasome activation in macrophages[5] and activated dendritic cells to secret IL-1β in a toll-like receptor (TLR)4-dependent manner, thereby amplifying Th1/Th17 immune responses and inflammation[6,7] These findings indicate that both intracellular fatty acids and extracellular LCFAs affect the functions of immune cells in vitro and in vivo. Upon stimulation via TCR engagement, iNKT cells rapidly secrete large amounts of various cytokines, thereby playing an important role in the regulation of inflammatory diseases[10,11] It has not been reported whether de novo fatty acids or extracellular saturated and unsaturated LCFAs affect the function of innate T cells including iNKT cells. Our experiments demonstrate that saturated LCFAs inhibit IL-4 and IFN-γ production in iNKT cells by promoting t-bet and gata-3 mRNA degradation via regulated IRE1α-dependent decay (RIDD), thereby attenuating iNKT cell-mediated joint inflammation

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