A subset of five human mitochondrial formyl peptides mimics bacterial peptides and functionally deactivates human neutrophils

Abstract

Therapeutic, Level IV.

Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation

“…Accompanying the impairment we observed in ex vivo NET formation was a significant trauma-induced elevation in the circulating levels of the mitochondrial-derived N-formylated peptide ND6. In a recent study, suppressed chemotactic responses toward CXCL1 and LTB 4 were reported for neutrophils pre-treated with synthetic ND6 (22), a finding that mirrored results of previous studies where prior exposure to bacterial-derived N-formylated peptides or ND6 respectively was shown to reduce neutrophil migration and ROS production upon secondary stimulation (10, 26). Adding to this growing body of literature that suggests a tolerising effect for mitochondrial-derived peptides on neutrophil function, we demonstrated that neutrophils pre-treated with whole mtDAMP preparations, but not purified mtDNA, exhibited significantly reduced NET production following PMA stimulation.…”

“…Furthermore, we showed that the trauma-induced reduction in NET formation could be replicated in vitro by treating neutrophils isolated from healthy donors with mtDAMPs prior to secondary stimulation. Thus, our data provides support for the emerging concept of mtDAMP-induced tolerance, where the post-injury release of mtDAMPs into the circulation has been proposed to contribute to the neutrophil dysfunction that develops in the aftermath of traumatic injury (10, 22).…”

“…For instance, it has been shown in vitro that monocytes pre-exposed to mtDNA (25) and neutrophils pre-treated with whole mtDAMP preparations (23) exhibit impaired cytokine production and calcium mobilization respectively upon secondary stimulation. Furthermore, a significant reduction in stimulus-induced ROS production and transmigration was reported for neutrophils pre-exposed to bacterial-derived or synthetic N-formylated peptides (10, 22, 26), both of which signal through the same formyl peptide receptor (FPR) as mitochondrial-derived formyl peptides. Based on these observations, the concept of mtDAMP-induced tolerance has been coined and proposed to be a potential mechanistic explanation for the state of peripheral neutrophil dysfunction that develops in the aftermath of major trauma (10, 22).…”

“…Trauma-associated tissue damage results in the release into the circulation of damage-associated molecular patterns (DAMPs), a collection of cytosolic, mitochondrial and nuclear-derived proteins, and DNA (14, 22, 23). Whilst renowned for their role in immune activation (23, 24), data are emerging that suggests mitochondrial-derived DAMPs (mtDAMPs), which include N-formylated peptides and mitochondrial DNA (mtDNA), possess immune tolerising properties.…”

Neutrophil chemoattractant receptors in health and disease: double-edged swords

“…Mitochondrial DAMPs induce Ca 2+ signaling and MAPK activation in human neutrophils, mediate chemotaxis and activation of the oxidative burst, promote the release of MMP-9 and CXCL8 by these cells, and may suppress cellular responses to CXCL1, LTB 4 and fMLF. 97,98 Mitochondrial DAMPs were abundantly present in bronchoalveolar fluids and serum from patients with acute respiratory distress syndrome, and deficiency or inhibition of FPR1 resulted in reduced inflammation in a murine model of this disease. 99 Additionally, high levels of mitochondrial DAMPs were associated with the development of primary graft dysfunction in lung transplantation patients.…”