Transducin-like enhancer of split 3 protects against lipopolysaccharide-induced inflammation through DEAD-box helicase 5–activating transcription factor 1–protein phosphatase 2 regulatory subunit

Sep 29, 2026

Sepsis is a life-threatening systemic inflammatory response disorder driven by excessive immune activation, and identifying inhibitory regulators of innate inflammation is critical for treatment. This study investigates how transducin-like enhancer of split 3 (TLE3) modulates inflammatory signaling in macrophages under lipopolysaccharide challenge. Multi-level experiments in patients, mouse models, and cultured macrophages show TLE3 restrains LPS-triggered cytokine release by influencing the DDX5–ATF1–PPP2R5A axis, enhancing PP2A activity and attenuating NF-κB and MAPK signaling, thereby protecting against acute systemic inflammation, organ injury, and death.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Article history

Abstract

Introduction

Objectives

Methods

Results

Conclusion

Journal of Advanced Research 79 (2026) 661–677 Contents lists available at ScienceDirect Journal of Advanced Research journal [homepage: www. elsevier. com/locate/jare](homepage: www. elsevier. com/locate/jare) Transducin-like enhancer of split 3 protects against lipopolysaccharideinduced inﬂammation through DEAD-box helicase 5–activating transcription factor 1–protein phosphatase 2 regulatory subunit 5A signaling TLE3 Attenuates LPS Inﬂammation via DDX5-ATF1-PPP2R5A Signaling Di Fan a,d, 1, Yi Zhong a,e, 1, Yin Dong a,f, Meng Du a,b,c,g, Kai Huang a,b,c,⁎, Xiaoguang Li a,b,c,⁎ a Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China b Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan 430022, China c Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan 430022, China d Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China e Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China f Cardiovascular Center, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China g Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China h i g h l i g h t s • TLE3 is upregulated in macrophages from septic survivors or with LPS stimulation. • Macrophage TLE3 mitigates LPSinduced inﬂammation in vivo, ex vivo and in vitro. • TLE3-DDX5-ATF1-PPP2R5A axis modulates the innate inﬂammatory signal in macrophage. g r a p h i c a l a b s t r a c t a r t i c l e i n f o Article history: Received 29 December 2024 Revised 14 March 2025 Accepted 21 March 2025 Available online 23 March 2025 Keywords: Transducin-like enhancer of split 3 DEAD-box helicase 5 Monocyte-derived macrophages Lipopolysaccharide-induced inﬂammation Sepsis a b s t r a c t Introduction: Sepsis consists of life-threatening multi-organ dysfunction caused by an excessive systemic inﬂammatory response to infection. Therefore, identifying negative regulators of innate inﬂammation is crucial for treating this condition. Objectives: In this study, we aimed to understand how transducin-like enhancer of split 3 (TLE3) regulates inﬂammatory responses. Methods: We detected Tle3 changes in sepsis patients by analyzing public databases, which were conﬁrmed in septic survivors, septic mouse models, and inﬂammatory macrophages using Western blotting, qRT-PCR, and immunohistochemistry staining. We investigated the role and mechanism of TLE3 in sepsis by utilizing bone marrow-transplantation (BMT) and adenovirus-infected mice. Furthermore, ProteinProtein Docking, BiFC, LC-MS/MS analysis, CUT & Tag-seq, and CHIP experiments were utilized to disclose the mechanism underlying TLE3 involving macrophage inﬂammation. ⁎ Corresponding authors at: Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. E-mail addresses: [huangkai1@hust.edu.cn](huangkai1@hust.edu.cn) (K. Huang), [lxg@hust.edu.cn](lxg@hust.edu.cn) (X. Li). 1 D.F, Y.Z contributed equally to this work. [https://doi.org/10.1016/j.jare.2025.03.041](https://doi.org/10.1016/j.jare.2025.03.041) 2090-1232/© 2025 The Author(s). Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). D. Fan, Y. Zhong, Y. Dong et al. Journal of Advanced Research 79 (2026) 661–677 Results: In this study, we found that Tle3 tran

FAQs

What is the main aim of this study on TLE3 in sepsis?

To clarify how transducin-like enhancer of split 3 (TLE3) regulates inflammatory responses during sepsis, especially in macrophages under LPS stimulation.

How is TLE3 expression related to sepsis outcomes in the study?

The study reports that Tle3 transcript is upregulated in peripheral blood samples of sepsis survivors and decreased in non-survivors, indicating a role in sepsis outcomes.

What mechanism does the study propose for how TLE3 reduces LPS-induced inflammation?

TLE3 is described to interact with DDX5, promoting its cytoplasmic retention, which decreases transcription of DDX5/ATF1-targeted Ppp2r5a; reduced PPP2R5A increases PP2A activity and promotes dephosphorylation of NF-κB and MAPK.

Sep 29, 2026

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