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Circulating mitochondrial DAMPs cause inflammatory responses to injury

Abstract

Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis1. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors2. Similarly, cellular injury can release endogenous ‘damage’-associated molecular patterns (DAMPs) that activate innate immunity3. Mitochondria are evolutionary endosymbionts that were derived from bacteria4 and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca2+ flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial ‘enemies within’ by cellular injury is a key link between trauma, inflammation and SIRS.

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Figure 1: PMN [Ca2+]i responses to MTD.
Figure 2: MTDs activate PMNs.
Figure 3: Mitochondrial DNA activates PMN through CpG/TLR9 interactions.
Figure 4: MTDs cause systemic inflammation and organ injury in vivo.

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Acknowledgements

This work is supported by a National Institute of General Medical Sciences grant and a Department of Defense CDMRP/DRMRP hypothesis development award (to C.J.H.).

Author Contributions Experiments were conceived and designed by C.J.H., Q.Z., K.I. and W.J. Experiments were performed by Q.Z., M.R., Y.C., Y.S., W.J., K.B. and T.S. Data were analysed by Q.Z. and C.J.H. The paper was written by Q.Z., M.R. and C.J.H.

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Correspondence to Carl J. Hauser.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-2 and Supplementary Figures 1-7 with Legends. (PDF 1430 kb)

Supplementary Video 1

In this video Human PMN are seen to migrate toward a pipette tip releasing fMLF. (MOV 3503 kb)

Supplementary Video 2

In this video Human PMN migrate toward an identical pipette tip releasing MTD. (MOV 3866 kb)

Supplementary Video 3

In this video Human PMN fail to migrate toward a pipette tip releasing an equal volume of MTD in the presence of the formyl peptide receptor inhibitor cyclosporin H (CsH). (MOV 3863 kb)

Supplementary Video 4

In this video Human PMN fail to migrate toward a pipette tip releasing an equal volume of MTD in the presence of antibodies to formyl peptide receptor-1 (FPR1). (MOV 3865 kb)

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Zhang, Q., Raoof, M., Chen, Y. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010). https://doi.org/10.1038/nature08780

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