The formyl peptide fMLF primes platelet activation and augments thrombus formation

Abstract

The role of formyl peptide receptor 1 (FPR1) and its ligand, fMLF, in the regulation of platelet function, hemostasis, and thrombosis is largely unknown. Fpr1‐deficient mice and selective inhibitors for FPR1 were used to investigate the function of fMLF and FPR1 in platelets. N‐formyl‐methionyl‐leucyl‐phenylalanine primes platelet activation and augments thrombus formation, mainly through FPR1 in platelets. Formyl peptide receptor 1 plays a pivotal role in the regulation of platelet function. Background Formyl peptide receptors (FPRs) play pivotal roles in the regulation of innate immunity and host defense. The FPRs include three family members: FPR1, FPR2/ALX, and FPR3. The activation of FPR1 by its high‐affinity ligand, N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLF) (a bacterial chemoattractant peptide), triggers intracellular signaling in immune cells such as neutrophils and exacerbates inflammatory responses to accelerate the clearance of microbial infection. Notably, fMLF has been demonstrated to induce intracellular calcium mobilization and chemotaxis in platelets that are known to play significant roles in the regulation of innate immunity and inflammatory responses. Despite a plethora of research focused on the roles of FPR1 and its ligands such as fMLF on the modulation of immune responses, their impact on the regulation of hemostasis and thrombosis remains unexplored. Objective To determine the effects of fMLF on the modulation of platelet reactivity, hemostasis, and thrombus formation. Methods Selective inhibitors for FPR1 and Fpr1‐deficient mice were used to determine the effects of fMLF and FPR1 on platelets using various platelet functional assays. Results N‐formyl‐methionyl‐leucyl‐phenylalanine primes platelet activation through inducing distinctive functions and enhances thrombus formation under arterial flow conditions. Moreover, FPR1 regulates normal platelet function as its deficiency in mouse or blockade in human platelets using a pharmacological inhibitor resulted in diminished agonist‐induced platelet activation. Conclusion Since FPR1 plays critical roles in numerous disease conditions, its influence on the modulation of platelet activation and thrombus formation may provide insights into the mechanisms that control platelet‐mediated complications under diverse pathological settings.

Deletion of Annexin A1 in Mice Upregulates the Expression of Its Receptor, Fpr2/3, and Reactivity to the AnxA1 Mimetic Peptide in Platelets

“…While the modulatory effects of ANXA1 and ANXA1 Ac2-26 during inflammation have been extensively studied in numerous disease models, their importance in platelet-mediated thromboinflammation is not yet fully understood. Recently, we reported the significance of FPRs and some of their ligands such as an antimicrobial peptide, LL37 [ 20 , 21 ], and a bacterial formyl peptide, fMLF [ 22 ], in the regulation of platelet function. Due to the critical roles of platelets at the interface between thrombosis and inflammation [ 3 ], the detailed characterisation of inflammatory receptors such as FPR2/ALX will pave the way to the development of novel therapeutic strategies to control exacerbated thromboinflammatory responses during pathological conditions.…”

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

“…NADPH oxidase (NOX) is an enzyme functional in many types of leukocytes catalyzing the production of SORA, which are sequestered in leukocytes to damage the membranes of invading pathogens. NOX activity was found to increase actin glutathionylation in neutrophils which was reversed with both DPI, an inhibitor of its activity, and DTT for reduction of the GSSP species ( Sakai et al, 2012 ; Salamah et al, 2019 ). This indicates that modulation of oxidants proves beneficial in prevention of actin glutathionylation.…”

Expression and function of receptors for the formylated peptides in granulocytes of the patients with rheumatoid arthritis

“…Например, в изолированных моноцитах человека активация FPR1 усиливает высвобождение IL-8, а также влияет на созревание, миграцию и фенотип дендритных клеток [11]. Также было обнаружено, что fMLF через FPR1 стимулирует активацию тромбоцитов и способствует образованию тромбов в артериях [32]. Недавно Prevete и соавт.…”