Eui-Soon Park ^1,†, Hyoeun Jeon ^1,†, Nari Lee ¹, Jiyeon Yu ¹, Hye-Won Park ¹, Takashi Satoh ², Shizuo Akira ³, Tatsuo Furuyama ⁴, Chul-Ho Lee ⁵, Jong-Soon Choi ⁶ and Jaerang Rho ^*,1

¹Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, Korea
²Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
³Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
⁴Department of Molecular Genetics and Geriatric Research, National Institute for Longevity Sciences, Kumamoto University, Kumamoto, Japan
⁵Laboratory Animal Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Korea
⁶Division of Life Science, Korea Basic Science Institute (KBSI), Daejeon, Korea

†These authors contributed equally to this work
*Corresponding author: correspondence to Jaerang Rho

Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important for innate immunity. Here, we show that T-cell death-associated gene 51 (TDAG51/PHLDA1) is a novel regulator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3ζ to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a regulator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.