Journal of advanced research · 2025
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 5A signaling.
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Fan Di, Zhong Yi, Dong Yin, Du Meng, Huang Kai, Li Xiaoguang
Аннотация
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, Protein-Protein Docking, BiFC, LC-MS/MS analysis, CUT & Tag-seq, and CHIP experiments were utilized to disclose the mechanism underlying TLE3 involving macrophage inflammation.
RESULTS: In this study, we found that Tle3 transcript is upregulated in peripheral blood samples of sepsis survivors and is decreased in non-survivors, suggesting the critical role of TLE3 in sepsis outcomes. TLE3 is also upregulated in lipopolysaccharide (LPS)-stimulated human monocyte-derived macrophages (MDMs), murine bone marrow-derived macrophages (BMDMs), and septic mice. Gain-of- and loss-of-function of TLE3 in LPS-stimulated murine BMDMs, human MDMs, and mouse models of sepsis showed that TLE3 alleviates LPS-induced cytokine production, as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activation in macrophages, which protects against LPS-induced acute systemic inflammation, multi-organ injury, and death caused by sepsis. Mechanistically, upregulated TLE3 interacts with the transcriptional coactivator, DEAD-box helicase 5 (DDX5), promoting its retention in the cytoplasm and ultimately decreasing transcription of the DDX5/ activating transcription factor 1 (ATF1)-targeted gene Ppp2r5a. Furthermore, the TLE3-DDX5-ATF1 axis downregulates PPP2R5A, a negative regulatory subunit of protein phosphatase 2A (PP2A), thereby increasing PP2A activity and promoting the dephosphorylation of NF-κB and MAPK.
CONCLUSION: Our study shows that TLE3 represents a novel suppressor of LPS-induced inflammatory signaling in macrophages.
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, Protein-Protein Docking, BiFC, LC-MS/MS analysis, CUT & Tag-seq, and CHIP experiments were utilized to disclose the mechanism underlying TLE3 involving macrophage inflammation.
RESULTS: In this study, we found that Tle3 transcript is upregulated in peripheral blood samples of sepsis survivors and is decreased in non-survivors, suggesting the critical role of TLE3 in sepsis outcomes. TLE3 is also upregulated in lipopolysaccharide (LPS)-stimulated human monocyte-derived macrophages (MDMs), murine bone marrow-derived macrophages (BMDMs), and septic mice. Gain-of- and loss-of-function of TLE3 in LPS-stimulated murine BMDMs, human MDMs, and mouse models of sepsis showed that TLE3 alleviates LPS-induced cytokine production, as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activation in macrophages, which protects against LPS-induced acute systemic inflammation, multi-organ injury, and death caused by sepsis. Mechanistically, upregulated TLE3 interacts with the transcriptional coactivator, DEAD-box helicase 5 (DDX5), promoting its retention in the cytoplasm and ultimately decreasing transcription of the DDX5/ activating transcription factor 1 (ATF1)-targeted gene Ppp2r5a. Furthermore, the TLE3-DDX5-ATF1 axis downregulates PPP2R5A, a negative regulatory subunit of protein phosphatase 2A (PP2A), thereby increasing PP2A activity and promoting the dephosphorylation of NF-κB and MAPK.
CONCLUSION: Our study shows that TLE3 represents a novel suppressor of LPS-induced inflammatory signaling in macrophages.