2. Academic Validation
  3. Baicalein upregulates macrophage TREM2 expression via TrKB-CREB1 pathway to attenuate acute inflammatory injury in acute-on-chronic liver failure

Baicalein upregulates macrophage TREM2 expression via TrKB-CREB1 pathway to attenuate acute inflammatory injury in acute-on-chronic liver failure

  • Int Immunopharmacol. 2024 Sep 30:139:112685. doi: 10.1016/j.intimp.2024.112685.
Jia Chen 1,  Qiongchi Zhang 2,  Wenxiong Xu 1,  Zhipeng Li 1,  Xiyao Chen 1,  Qiumin Luo 1,  Dong Wang 3,  Liang Peng 4
Affiliations

Affiliations

  • 1 Department of Infectious Diseases and Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Department of Orthopedics, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Department of Orthopedics, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. Electronic address: wado110@163.com.
  • 4 Department of Infectious Diseases and Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China. Electronic address: pliang@mail.sysu.edu.cn.
PMID: 39047449 DOI: 10.1016/j.intimp.2024.112685
Abstract

Objective: Acute-on-chronic liver failure (ACLF) is a syndrome characterized by a high short-term mortality rate, and effective interventions are still lacking. This study aims to investigate whether the small molecule baicalein can mitigate ACLF and elucidate the molecular mechanisms.

Methods: The ACLF mouse model was induced through chronic liver injury using carbon tetrachloride, followed by acute inflammation induction with lipopolysaccharide (LPS). Baicalein was administered through intraperitoneal injection to explore its therapeutic effects. In vitro experiments utilized the iBMDM macrophage cell line to investigate the underlying mechanisms. Peripheral blood was collected from clinical ACLF patients for validation.

Results: In the LPS-induced ACLF mouse model, baicalein demonstrated a significant reduction in acute inflammation and liver damage, as evidenced by histopathological evaluation, liver function analysis, and inflammatory marker measurements. Transcriptomic analysis, coupled with Molecular Biology experiments, uncovered that baicalein exerts its effects in ACLF by activating the TrKB-CREB1 signaling axis to upregulate the surface expression of the TREM2 receptor on macrophages. This promotes M2 macrophage polarization and activates efferocytosis, thereby inhibiting inflammation and alleviating liver damage. Furthermore, we observed a substantial negative correlation between postoperative peripheral blood plasma soluble TREM2 (sTREM2) levels and inflammation, as well as adverse outcomes in clinical ACLF patients.

Conclusion: Baicalein plays a protective role in ACLF by enhancing the surface expression of the TREM2 receptor on macrophages, leading to the suppression of inflammation, mitigation of liver damage, and a reduction in mortality. Additionally, plasma sTREM2 emerges as a critical indicator for predicting adverse outcomes in ACLF patients.

Keywords

Acute-on-chronic liver failure; Baicalein; Triggering receptor expressed on myeloid cells 2.

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