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

Kaczmarek, Elzbieta PhD; Hauser, Carl J. MD; Kwon, Woon Yong MD, PhD; Riça, Ingred PhD; Chen, Li MD; Sandler, Nicola MBBS; Otterbein, Leo E. PhD; Campbell, Yan PhD; Cook, Charles H. MD; Yaffe, Michael B. MD, PhD; Marusich, Michael F. PhD; Itagaki, Kiyoshi PhD

Journal of Trauma and Acute Care Surgery: November 2018 - Volume 85 - Issue 5 - p 936–943
doi: 10.1097/TA.0000000000001971

BACKGROUND Trauma causes inflammation by releasing mitochondria that act as Danger-Associated Molecular Patterns (DAMPs). Trauma also increases susceptibility to infection. Human mitochondria contain 13 N-formyl peptides (mtFPs). We studied whether mtFPs released into plasma by clinical injury induce neutrophil (PMN) inflammatory responses, whether their potency reflects their similarity to bacterial FPs and how their presence at clinically relevant concentration affects PMN function.

METHODS N-terminal sequences of the 13 mtFPs were synthesized. Changes in human PMN cytosolic Ca2+ concentration ([Ca2+]i) and chemotactic responses to mtFPs were studied. Sequence similarity of mtFPs to the canonical bacterial peptide f-Met-Leu-Phe (fMLF/fMLP) was studied using the BLOcks SUbstitution Matrix 62 (BLOSUM 62) system. The presence of mtFPs in plasma of trauma patients was assayed by Enzyme-linked immunosorbent assay (ELISA). The effects of the most potent mtFP (ND6) on PMN signaling and function were then studied at ambient clinical concentrations by serial exposure of native PMN to ND6, chemokines and leukotrienes.

RESULTS Five mtFPs (ND6, ND3, ND4, ND5, and Cox 1) induced [Ca2+]i flux and chemotaxis in descending order of potency. Evolutionary similarity to fMLF predicted [Ca2+]i flux and chemotactic potency linearly (R2 = 0.97, R2 = 0.95). Chemoattractant potency was also linearly related to [Ca2+]i flux induction (R2 = 0.92). Active mtFPs appear to circulate in significant amounts immediately after trauma and persist through the first week. The most active mtFP, ND6, suppresses responses to physiologic alveolar chemoattractants (CXCL-1, leukotriene B4) as well as to fMLF where CXCL-1 and leukotriene B4 do not suppress N-formyl peptide receptor (FPR)-1 responses to mtFPs. Prior FPR-1 inhibition rescues PMN from heterologous suppression of CXCR-1 and BLT-1 by mtFPs.

CONCLUSION The data suggest mtFPs released by injured tissue may attract PMN to trauma sites while suppressing PMN responses to other chemoattractants. Inhibition of mtFP-FPR1 interactions might increase PMN recruitment to lung bacterial inoculation after trauma. These findings suggest new paradigms for preventing infections after trauma.

LEVEL OF EVIDENCE Therapeutic, Level IV.

From the Department of Surgery and Center for Vascular Biology Research (E.K.), Department of Surgery (C.J.H., L.C., N.S., L.E.O., C.H.C., K.I.), Department of Surgery, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts; Department of Emergency Medicine (W.Y.K.), Seoul National University College of Medicine, Seoul, Republic of Korea; Massachusetts Institute of Technology (I.R., M.B.Y.), Cambridge, Massachusetts; and mAbDx, Inc (Y.C., M.M.), Eugene, Oregon.

Submitted: February 12, 2018, Revised: April 19, 2018, Accepted: April 27, 2018, Published online: May 22, 2018.

This study was presented at the 48th Annual Meeting of the Western Trauma Association, February 25-March 2, 2018 in Whistler, British Columbia.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (

Address for reprints: Kiyoshi Itagaki, PhD, 3 Blackfan Circle, CLS604, Boston, MA 02115; email:; Carl J. Hauser, MD, Suite 2G, 110 Francis St, Boston, MA 02115; email:

© 2018 Lippincott Williams & Wilkins, Inc.