Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome

Abstract

BackgroundAcute respiratory distress syndrome (ARDS) is an often fatal neutrophil-dominant lung disease. Although influenced by multiple proinflammatory mediators, identification of suitable therapeutic candidates remains elusive. We aimed to delineate the presence of mitochondrial formylated peptides in ARDS and characterise the functional importance of formyl peptide receptor 1 (FPR1) signalling in sterile lung inflammation.MethodsMitochondrial formylated peptides were identified in bronchoalveolar lavage fluid (BALF) and serum of patients with ARDS by liquid chromatography–tandem mass spectrometry. In vitro, human neutrophils were stimulated with mitochondrial formylated peptides and their effects assessed by flow cytometry and chemotaxis assay. Mouse lung injury was induced by mitochondrial formylated peptides or hydrochloric acid. Bone marrow chimeras determined the contribution of myeloid and parenchymal FPR1 to sterile lung inflammation.ResultsMitochondrial formylated peptides were elevated in BALF and serum from patients with ARDS. These peptides drove neutrophil activation and chemotaxis through FPR1-dependent mechanisms in vitro and in vivo. In mouse lung injury, inflammation was attenuated in Fpr1−/− mice, effects recapitulated by a pharmacological FPR1 antagonist even when administered after the onset of injury. FPR1 expression was present in alveolar epithelium and chimeric mice demonstrated that both myeloid and parenchymal FPR1 contributed to lung inflammation.ConclusionsWe provide the first definitive evidence of mitochondrial formylated peptides in human disease and demonstrate them to be elevated in ARDS and important in a mouse model of lung injury. This work reveals mitochondrial formylated peptide FPR1 signalling as a key driver of sterile acute lung injury and a potential therapeutic target in ARDS.

Mitocryptides from Human Mitochondrial DNA–Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties

“…Our data demonstrating that these host-derived formylated MCTs are highly potent in activating neutrophils support the notion that, when released from disintegrating mitochondria, these molecules may play important roles in the inflammatory response resulting from tissue injury (21,23,24). Indeed, elevated levels of mitochondrialderived formyl peptides have been detected in bronchoalveolar lavage fluid and serum in patients with acute respiratory distress syndrome (54). Activation of circulating neutrophils by mitochondrialderived formyl peptides during cell damage has also been described in trauma patients and has been the suggested cause of systemic inflammatory response syndrome with sepsis-like clinical manifestations (25).…”

Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction

“…Recently, FPR1 was shown to promote pulmonary injury in a mouse model of acute respiratory distress syndrome, 23 Figure 5D). Altogether, these data show that FPR1 expression on graft-infiltrating cells is sufficient to promote graft tissue damage.…”

“…Recently, FPR1 was shown to promote pulmonary injury in a mouse model of acute respiratory distress syndrome, 23 but whether it promotes inflammatory responses to lung transplants remains to be determined. Accordingly, we assessed lung graft injury in mouse recipients treated with cyclosporine H (Cy-H), an FPR1 inhibitor.…”

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

“…FPRs constitute a small group of 7-transmembrane domain, G-protein-coupled receptors that are expressed not only on neutrophils, monocytes and dendritic cells but also on hepatocytes, endothelial cells and cells of the nervous system (He and Ye, 2017). Indeed, a recent study has suggested a pathogenic role of mitochondrial NFPs in human disease (Dorward et al, 2017). In this study, mitochondrial NFPs appear to be increased in the intra-alveolar space of lungs and circulation of patient with acute respiratory destress syndrome (ARDS) and mitochondrial NFPs-driven formyl peptide receptor 1 signaling seems to mediate an important role in the pathogenesis of sterile lung inflammation (Dorward et al, 2017).…”

“…Indeed, a recent study has suggested a pathogenic role of mitochondrial NFPs in human disease (Dorward et al, 2017). In this study, mitochondrial NFPs appear to be increased in the intra-alveolar space of lungs and circulation of patient with acute respiratory destress syndrome (ARDS) and mitochondrial NFPs-driven formyl peptide receptor 1 signaling seems to mediate an important role in the pathogenesis of sterile lung inflammation (Dorward et al, 2017). …”