TDAG51 promotes transcription factor FoxO1 activity during LPS‐induced inflammatory responses.

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. Synopsis: Toll‐like receptor (TLR) signaling is tightly controlled during inflammatory responses. Here, TDAG51/PHLDA1 is identified as a new interactor and regulator of transcription factor FoxO1, stimulating inflammatory mediator production upon LPS challenge. TDAG51 expression is induced during the LPS‐induced inflammatory response in macrophages.TDAG51 interacts with the transcription factor FoxO1 and competitively inhibits 14‐3‐3흵 bindingTDAG51‐FoxO1 interaction and reduced 14‐3‐3흵 binding enhances FoxO1 nuclear accumulation, thereby promoting inflammatory mediator expression.TDAG51 deficiency attenuates LPS‐induced lethal shock by weakening the inflammatory response in mice. [ABSTRACT FROM AUTHOR]