Formyl Peptide Receptor Signaling in Immune Responses

Formyl peptide receptors (FPRs) constitute a family of G-protein-coupled receptors expressed predominantly on phagocytic leukocytes and certain non-haematopoietic cells. They recognise N-formylated peptides derived from bacterial pathogens or mitochondrial proteins released during cell injury, thereby serving as a rapid sensor of infection and tissue damage. Upon ligand engagement, FPRs initiate downstream signalling cascades involving heterotrimeric G-proteins, activation of phospholipase C, phosphoinositide 3-kinase and mitogen-activated protein kinases, and mobilisation of intracellular calcium. These events drive chemotaxis, degranulation and generation of reactive oxygen species, orchestrating both pro-inflammatory and pro-resolving programmes depending on the ligand and receptor isoform. FPR1 is classical for high-affinity bacterial peptide recognition, whereas FPR2 displays versatile ligand promiscuity, including lipids and peptides with either pro- or anti-inflammatory bias. The differential engagement of downstream pathways underpins the concept of biased agonism, offering routes to modulate inflammation without compromising host defence. Beyond innate immunity, FPR signalling contributes to tissue repair, cardiovascular homeostasis and resolution of chronic inflammation, making these receptors attractive targets for therapeutic intervention in infection, ischaemia-reperfusion injury and inflammatory disorders.

Research from Nature Portfolio

Recent studies have demonstrated the potential of biased small-molecule agonists to fine-tune FPR-mediated signalling and achieve improved tissue protection. One seminal report described a dual FPR1/FPR2 agonist that selectively avoids calcium mobilisation while preserving ERK1/2 and Akt activation. This biased ligand afforded superior cardioprotection in in vitro models of myocardial stress and in vivo infarction, highlighting the therapeutic promise of pathway-selective FPR modulation.

Advances in structural biology have further clarified how FPRs accommodate chemically diverse ligands. A high-resolution cryo-electron microscopy structure of the FPR2–Gi complex revealed a widely open extracellular pocket with amphiphilic features that account for promiscuous peptide and lipid binding. Computational docking combined with mutagenesis identified key residues governing ligand recognition and receptor activation, providing a molecular framework to design next-generation agonists or antagonists.

Formyl Peptide Receptor Signaling in Immune Responses publication trend

The graph below shows the total number of articles in formyl peptide receptor signaling in immune responses across all publications each year (not limited to Nature Index journals).

Technical terms

Formyl peptide receptor (FPR): A class of G-protein-coupled receptors that detect N-formylated peptides from bacteria or mitochondria to trigger immune cell activation.

Biased agonism: The ability of a ligand to preferentially activate certain signalling pathways over others via the same receptor.

Efferocytosis: The process by which phagocytes engulf and clear apoptotic cells, promoting resolution of inflammation.

Cryo-electron microscopy (cryo-EM): A structural biology technique that visualises proteins at near-atomic resolution under cryogenic conditions.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that are generated during phagocyte activation and contribute to microbial killing and cell signalling.

References

1. Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage. Cardiovascular Research (2024).
2. Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice. Nature Communications (2017).
3. Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nature Communications (2020).
4. Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation. EMBO Molecular Medicine (2023).
5. Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase. Antioxidants (2024).
6. The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition. Molecules (2017).