Formyl Peptide Receptor Type 2 Deficiency in Myeloid Cells Amplifies Sepsis-Induced Cardiac Dysfunction

Area of Science:

• Immunology
• Cardiovascular Biology
• Microbiology

Background:

• Formyl peptide receptor 2 (FPR2) is a pro-resolving receptor involved in modulating inflammatory responses.
• Previous studies highlighted FPR2's role in polymicrobial sepsis using global knockout mice.
• Understanding the specific cellular mechanisms of FPR2 in sepsis requires targeted investigation.

Purpose of the Study:

• To investigate the cellular mechanisms of humanized FPR2 (hFPR2) in polymicrobial sepsis.
• To determine the role of myeloid cell-specific FPR2 deficiency in sepsis-induced cardiac dysfunction and immune response.
• To evaluate the therapeutic potential of the FPR2 agonist annexin A1 (AnxA1) in a myeloid cell-specific FPR2 knockout model.

Main Methods:

• Utilized a humanized FPR2 (hFPR2) mouse colony and myeloid cell-specific hFPR2 knockout (KO) mice.
• Induced polymicrobial sepsis using the cecal ligation and puncture (CLP) model.
• Assessed cardiac function via echocardiography, clinical outcomes, bacterial clearance, and immune cell populations in cardiac and peritoneal tissues.

Main Results:

• Myeloid cell-specific hFPR2 deficiency exacerbated cardiac dysfunction, worsened clinical outcome, and impaired bacterial clearance in septic mice.
• KO mice exhibited increased pro-inflammatory monocytes and neutrophils, with reduced M2-like macrophages in the heart.
• Annexin A1 treatment improved cardiac function in hFPR2 mice but had limited effects in KO mice, failing to promote M2 macrophage polarization.

Conclusions:

• FPR2 deficiency in myeloid cells critically exacerbates cardiac dysfunction and adverse clinical outcomes during polymicrobial sepsis.
• Myeloid cell FPR2 plays a crucial role in orchestrating the host immune response, including macrophage polarization.
• Targeting FPR2 with AnxA1 demonstrates therapeutic potential, particularly in settings with intact myeloid cell FPR2 expression.