Novel Resolvin D2 Receptor Axis in Infectious Inflammation

Area of Science:

• Immunology
• Pharmacology
• Molecular Biology

Background:

• Acute inflammation resolution is an active process mediated by specialized proresolving mediators like resolvin D2 (RvD2).
• RvD2 signals through the G protein-coupled receptor GPR18/DRV2.
• Understanding RvD2-DRV2-dependent mechanisms is key to developing new anti-inflammatory therapies.

Purpose of the Study:

• To investigate the role of the RvD2-DRV2 axis in resolving polymicrobial sepsis.
• To elucidate the intracellular signaling pathways activated by RvD2-DRV2 interaction.
• To assess the impact of RvD2-DRV2 on bacterial clearance and host survival.

Main Methods:

• Utilized DRV2-knockout (KO) mice to study RvD2-DRV2-dependent mechanisms.
• Induced polymicrobial sepsis via cecal ligation and puncture (CLP).
• Employed mass spectrometry-based lipid mediator metabololipidomics and mass cytometry (cytometry by time-of-flight) for analysis.

Main Results:

• RvD2 significantly increased survival, reduced hypothermia, and lowered bacterial titers in wild-type mice post-CLP, but this protection was abolished in DRV2-KO mice.
• DRV2-KO mice exhibited higher levels of pro-inflammatory leukotriene B4 and lower levels of specialized proresolving mediators in infectious exudates.
• RvD2 enhanced phosphorylation of CREB, ERK1/2, and STAT3 in wild-type macrophages and promoted phagocytosis of Escherichia coli, dependent on protein kinase A and STAT3.

Conclusions:

• Identified a critical RvD2/DRV2 signaling axis essential for activating intracellular pathways that enhance phagocytosis-mediated bacterial clearance.
• Demonstrated the RvD2-DRV2 pathway's role in improving survival and organ protection during infectious inflammation.
• Provided evidence for the therapeutic potential of targeting the RvD2-DRV2 axis in sepsis and other inflammatory conditions.