Tauroursodeoxycholic Acid Inhibits NF-κB/p300/H3K14ac to Attenuate Microglial Activation in Lipopolysaccharide-treated BV-2 Cells and Mice.

Tauroursodeoxycholic acid (TUDCA) shows therapeutic potential for neuroinflammation and related neuropsychiatric disorders. However, the intrinsic mechanism by which TUDCA counteracts microglial activation and neuroinflammation has not been clarified. In this study, the epigenetic mechanism through which TUDCA regulates inducible nitric oxide synthase (iNOS) generation to antagonize microglial activation was investigated in lipopolysaccharide (LPS)-treated microglial BV-2 cells and mice. The results confirmed the inhibitory effects of TUDCA on LPS-induced iNOS overgeneration, oxidative stress and microglial activation in BV-2 cells. Mechanistically, TUDCA inhibited the recruitment of NF-κB and the histone acetyltransferase p300 to the iNOS gene promoter and reduced the enrichment of histone H3 lysine 14 acetylation (H3K14ac), but not H3K9ac in LPS-stimulated BV-2 cells. Moreover, TUDCA inhibited the binding and co-localization of NF-κB and p300, and reduced the p300-bound H3K14ac in LPS-stimulated BV-2 cells. Although the bile acid nuclear receptor farnesoid X receptor (FXR) has been reported to inhibit the NF-κB signaling pathway, its content hardly changed among the groups, indicating TUDCA's effects independent of FXR in this context. In addition, molecular docking predicted specific binding between TUDCA and p300. Consistent with the cellular findings, TUDCA alleviated neuroinflammation and behavioral abnormalities in LPS-treated mice. TUDCA also attenuated microglial activation in the hippocampus and reduced brain H3K14ac level. In conclusion, TUDCA inhibited NF-κB/p300 activity and decreased H3K14ac enrichment at the iNOS gene promoter, thereby attenuating microglial activation in both LPS-treated BV-2 cells and mice.