Formyl Peptide Receptor-1 Blockade Prevents Receptor Regulation by Mitochondrial Danger-Associated Molecular Patterns and Preserves Neutrophil Function After Trauma

Abstract

Objectives-Trauma predisposes to systemic sterile inflammation (SIRS) as well as infection, but the mechanisms linking injury to infection are poorly understood. Mitochondrial debris (MTD) contains formyl peptides (mtFPs). These bind formyl peptide receptor-1 (FPR1), trafficking neutrophils (PMN) to wounds, initiating SIRS and wound healing. Bacterial FPs (bFPs) however, also attract PMN via FPR1. Thus mtFPs might suppress PMN antimicrobial function. Also, FPR1 blockade used to mitigate SIRS might predispose to sepsis. We examined how mtFPs impact PMN functions contributing to antimicrobial responses, and how FPR1 antagonists affect those functions. Design-Prospective study of human and murine PMN and clinical cohort analysis.Setting-University research laboratory and Level 1 trauma center. Patients-Trauma patients, volunteer controls.Animal subjects-C57Bl/6, FPR1, and FPR2 knockout mice.Interventions-Human and murine PMN functions were activated with autologous MTD, mtFPs or bFPs followed by chemokines or leukotrienes. The experiments were repeated using FPR1 antagonist cyclosporin H (CsH), 'designer' human FPR1 antagonists (POL7178 and POL7200) or

Circulating mitochondrialN-formyl peptides contribute to secondary nosocomial infection in patients with septic shock

“…Human PMN Isolation. Human PMNs and PBMCs were isolated from freshly drawn healthy volunteer blood (11,12). With the permission of the Institutional Review Board (IRB) of Seoul National University College of Medicine/Seoul National University Hospital (IRB number: 1605-044-760), we received written informed consent from healthy volunteers and obtained fresh blood from them for in vitro and ex vivo experiments.…”

“…Mitochondrial damage–associated molecular patterns (mtDAMPs) are released from injured tissues ( 11 – 14 ). MtDAMPs express at least two critical inflammatory molecular signatures: mitochondrial N -formyl peptides (mtFPs) and mitochondrial DNA (mtDNA) ( 15 , 16 ).…”

“…MtDAMPs express at least two critical inflammatory molecular signatures: mitochondrial N -formyl peptides (mtFPs) and mitochondrial DNA (mtDNA) ( 15 , 16 ). MtFPs bind to formyl peptide receptor-1 (FPR1) on the PMN membrane, desensitizing FPR1 and other GPCRs via internalization of the receptors ( 11 , 17 – 20 ). This step blocks the binding of chemoattractants to a broad range of GPCRs potentially suppressing PMN migration toward bacterial inoculation sites ( 11 , 17 – 20 ).…”

“…MtFPs bind to formyl peptide receptor-1 (FPR1) on the PMN membrane, desensitizing FPR1 and other GPCRs via internalization of the receptors ( 11 , 17 – 20 ). This step blocks the binding of chemoattractants to a broad range of GPCRs potentially suppressing PMN migration toward bacterial inoculation sites ( 11 , 17 – 20 ). Our previous studies have shown that mtDAMPs released by extrapulmonary injuries can reduce bacterial clearance and so increase secondary pneumonia by suppressing PMN chemotaxis toward secondary stimuli and that FPR1 blockade prevented down-regulation of PMN chemotaxis by preserving non-FPR1 GPCRs after injury ( 11 , 21 , 22 ).…”

The Contribution of Chemoattractant GPCRs, Formylpeptide Receptors, to Inflammation and Cancer

“…More importantly, FPRs appear to be on top of a desensitization hierarchy, where FPRs seem to possess a "one directional desensitization" capacity vs. other chemoattractant GPCRs, especially chemokine GPCRs, through a protein kinase C mediated signaling pathway (27). Desensitization of chemokine receptors CCR5 and CXCR4 on immune cells by FPR ligands resulted in the loss of the capacity of these GPCRs to act as HIV fusion co-receptors therefore suggest a unique opportunity for development of novel anti-HIV therapeutic agents (28,29).…”