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Formyl Peptide Receptor Type 2 Deficiency in Myeloid Cells Amplifies Sepsis-Induced Cardiac Dysfunction
Jianmin Chen1,2, Shani Austin-Williams1, Caroline Elizabeth O'Riordan1
1William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK.
Abstract:
Using a global formyl peptide receptor (Fpr) 2 knockout mouse colony, we have reported the modulatory properties of this pro-resolving receptor in polymicrobial sepsis. Herein, we have used a humanized FPR2 (hFPR2) mouse colony, bearing an intact or a selective receptor deficiency in myeloid cells to dwell on the cellular mechanisms. hFPR2 mice and myeloid cell-specific hFPR2 KO (KO) mice were subjected to cecal ligation and puncture (CLP)-induced polymicrobial sepsis. Compared with hFPR2 mice, CLP caused exacerbated cardiac dysfunction (assessed by echocardiography), worsened clinical outcome, and impaired bacterial clearance in KO mice. This pathological scenario was paralleled by increased recruitment of pro-inflammatory monocytes and reduced M2-like macrophages within the KO hearts. In peritoneal exudates of KO mice, we quantified increased neutrophil and MHC II+ macrophage numbers but decreased monocyte/macrophage and MHC II- macrophage recruitment. hFPR2 upregulation was absent in myeloid cells, and local production of lipoxin A4 was reduced in septic KO mice. Administration of the FPR2 agonist annexin A1 (AnxA1) improved cardiac function in hFPR2 septic mice but had limited beneficial effects in KO mice, in which the FPR2 ligand failed to polarize macrophages toward an MHC II- phenotype. In conclusion, FPR2 deficiency in myeloid cells exacerbates cardiac dysfunction and worsens clinical outcome in polymicrobial sepsis. The improvement of cardiac function and the host immune response by AnxA1 is more effective in hFPR2-competent septic mice.
Insights
Formyl peptide receptor 2 (FPR2) deficiency in myeloid cells worsens polymicrobial sepsis outcomes, leading to cardiac dysfunction and impaired bacterial clearance. Annexin A1
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.
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