Ursodeoxycholic acid attenuates sepsis-associated platelet dysfunction through TREM2-linked signaling.

Area of Science:

• Immunology
• Hematology
• Pharmacology

Background:

• Sepsis presents a significant clinical challenge due to immune dysregulation and coagulopathy.
• Ursodeoxycholic acid (UDCA) shows potential therapeutic benefits in sepsis, but its underlying mechanisms are not fully understood.
• Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunoreceptor with emerging roles in platelet biology and immune responses.

Purpose of the Study:

• To investigate whether UDCA modulates platelet function in sepsis through TREM2.
• To explore the potential of UDCA as a therapeutic agent targeting sepsis-associated coagulopathy via TREM2.

Main Methods:

• Integrated strategy: retrospective analysis of 6476 sepsis patients (MIMIC-IV), causal mediation analysis, mechanistic studies in LPS-induced septic and TREM2-knockout mice.
• Computational docking to predict UDCA-TREM2 interaction.
• Prospective pilot study in 8 septic patients receiving UDCA.

Main Results:

• Retrospective analysis: UDCA associated with reduced hospital mortality, largely mediated by increased platelet counts.
• Mechanistic studies: UDCA increased platelet TREM2 expression, attenuated LPS-induced hyperactivation and downstream signaling in a TREM2-dependent manner.
• Pilot study: UDCA increased platelet counts and inhibited ADP-induced platelet aggregation in septic patients.

Conclusions:

• UDCA may improve sepsis outcomes by modulating platelet homeostasis through a TREM2-associated mechanism.
• Findings suggest TREM2 as a potential therapeutic target for sepsis-associated coagulopathy.
• Preliminary translational evidence supports UDCA's role in sepsis management.