• Mustafa Raoof, Qin Zhang, Kiyoshi Itagaki, and Carl J Hauser.
• Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
• J Trauma. 2010 Jun 1;68(6):1328-32; discussion 1332-4.

BackgroundTissue injury from mechanical trauma modulates innate immunity. The resultant systemic inflammatory response syndrome (SIRS) closely mimics clinical sepsis, and bacterial n-formyl peptides are septic mediators. Similar formyl peptides exist in mitochondria but little is known about their actions on human neutrophils (PMN).MethodsMitochondria were isolated from rat heptocytes and disrupted. Soluble mitochondrial degradation products (MDP) were used to stimulate human PMN. Cytosolic calcium ([Ca]i) responses to MDP were assayed with and without antibody blockade of formyl peptide receptor 1 (FPR-1) or formyl peptide receptor like-1 (FPRL-1). Chemotaxis toward MDP was assessed in trans-wells. Oxidative burst to MDP was assessed using carboxycarboxy-2', 7'-dichlorodihydrofluorescein diacetate.ResultsMDP caused [Ca]i responses similar to those caused by formyl-Met-Leu-Phe. [Ca]i responses were completely blocked by anti-FPR-1 antibodies, showing activation occurred via the high-affinity, G-protein-coupled FPR-1 receptor. MDP acted on FPR-1 to give chemotactic responses similar to 10 nM formyl-Met-Leu-Phe. MDP also caused dose-dependent oxidative burst.ConclusionFormylated mitochondrial proteins are potent immune activators. Acting through the FPR-1 receptor on professional phagocytes, MDP elicits [Ca]i release responses and Ca entry via G-protein-coupled pathways. MDP activates chemotaxis and respiratory burst. Our findings suggest a novel paradigm wherein one root cause of SIRS after trauma may be the release of mitochondrial fragments from mechanically damaged tissues. In this paradigm, mitochondrial debris "alarmins" alter host PMN phenotype, activating or suppressing immunity, predisposing to SIRS, sepsis or organ failure.

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