2. Academic Validation
  3. Acetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis

Acetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis

  • EMBO J. 2024 Sep 18. doi: 10.1038/s44318-024-00237-8.
Xue Li # 1 2 3,  Xiangrong Li # 4,  Pengpeng Huang 5,  Facai Zhang 5,  Juanjuan K Du 5,  Ying Kong 6,  Ziqiang Shao 5,  Xinxing Wu 5,  Weijiao Fan 5,  Houquan Tao 5,  Chuanzan Zhou 5,  Yan Shao 5,  Yanling Jin 5,  Meihua Ye 5,  Yan Chen 5,  Jong Deng 7,  Jimin Shao 8,  Jicheng Yue 7,  Xiaju Cheng 9,  Y Eugene Chinn 10 11
Affiliations

Affiliations

  • 1 Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital of Hangzhou Medical College, Hangzhou, China. snowlee@zju.edu.cn.
  • 2 Yantai Peninsular Cancer Center, Binzhou Medical University, Yantai, China. snowlee@zju.edu.cn.
  • 3 Life Science Research Institute, Zhejiang University, Hangzhou, China. snowlee@zju.edu.cn.
  • 4 Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 5 Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital of Hangzhou Medical College, Hangzhou, China.
  • 6 Department of Urology, the First Affiliated Hospital of Soochow University, Suzhou, China.
  • 7 Yantai Peninsular Cancer Center, Binzhou Medical University, Yantai, China.
  • 8 Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
  • 9 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China. xjcheng@suda.edu.cn.
  • 10 Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital of Hangzhou Medical College, Hangzhou, China. chinyue@suda.edu.cn.
  • 11 Yantai Peninsular Cancer Center, Binzhou Medical University, Yantai, China. chinyue@suda.edu.cn.
  • # Contributed equally.
PMID: 39294473 DOI: 10.1038/s44318-024-00237-8
Abstract

Activation of the Toll-like Receptor 4 (TLR4) by Bacterial endotoxins in macrophages plays a crucial role in the pathogenesis of sepsis. However, the mechanism underlying TLR4 activation in macrophages is still not fully understood. Here, we reveal that upon lipopolysaccharide (LPS) stimulation, lysine acetyltransferase CBP is recruited to the TLR4 signalosome complex leading to increased acetylation of the TIR domains of the TLR4 signalosome. Acetylation of the TLR4 signalosome TIR domains significantly enhances signaling activation via NF-κB rather than IRF3 pathways. Induction of NF-κB signaling is responsible for gene expression changes leading to M1 macrophage polarization. In sepsis patients, significantly elevated TLR4-TIR acetylation is observed in CD16+ monocytes combined with elevated expression of M1 macrophage markers. Pharmacological inhibition of HDAC1, which deacetylates the TIR domains, or CBP play opposite roles in sepsis. Our findings highlight the important role of TLR4-TIR domain acetylation in the regulation of the immune responses in sepsis, and we propose this reversible acetylation of TLR4 signalosomes as a potential therapeutic target for M1 macrophages during the progression of sepsis.

Keywords

HDAC1 Inhibitor; Macrophage; NF-κB Signaling Pathway; Sepsis; TLR4-TIR Acetylation.

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