Background Mitochondria are the powerhouses of the cell, providing energy to the cell through oxidative phosphorylation. Possibly owing to their similarities with bacteria, however, mitochondria extruded from cells promote inflammation. Platelets are anucleated elements highly abundant in blood and are activated in rheumatic diseases. As platelets represent a major reservoir of mitochondria in blood circulation, we hypothesised that activated platelets could release their mitochondria in rheumatic diseases.
Materials and methods Human platelets were activated using synthetic immune complexes (IC) and mitochondrial extrusion was determined using electron microscopy and high sensitivity flow cytometry. To determine whether mitochondrial release could occur in vivo, the presence of extracellular mitochondria in blood of systemic lupus erythematosus (SLE) patients was monitored concomitantly with platelet activation by the assessment of surface P-selectin and of the activated form of glycoprotein IIbIIIa. As mice naturally lack the expression of the immunoglobulin G (IgG) Fc receptor FcyRIIA, the unique platelet receptor for IgG in humans, we included transgenic mice expressing FcyRIIA to our in vivo mechanistic investigations. Platelet activation and mitochondrial release were monitored upon intravenous injection of synthetic ICs in wild type (WT) and transgenic (Tg) FcyRIIA mice.
Results We found that on activation, platelets relocate their mitochondria toward the cell membrane and then release respiratory-competent mitochondria into the extracellular milieu, both as free organelles and encapsulated within vesicles called microparticles (MP). Extracellular mitochondria were internalised by bystander leukocytes and, importantly, induced leukocytes rolling and adhesion to the blood vessel wall, suggesting that neutrophils and/or endothelial cells are activated by extracellular mitochondria. Activated platelets were more abundant in SLE patients than control subjects, and were associated with IgG. Extracellular mitochondria, both encapsulated in platelet MPs or naked, were also observed in blood circulation in SLE, and were frequently associated with IgG. Mechanistically, ICs present in blood induce profound cell activation, which is dependent on platelet FcyRIIA and its signalling cascade.
Conclusions Platelets represent an important source of mitochondria, which release in blood upon stimulation of FcyRIIA, might promote systemic inflammation in SLE. Whether the blockade of FcyRIIA might represent an attractive avenue in SLE research, and whether platelet activation markers and extracellular mitochondria might be utilised as potential biomarkers for the stratification of lupus patients needs to be further considered.
Acknowledgements This study was supported by the Canadian Institutes of Health Research (to PRF and EB). EB is recipient of an award from the Canadian Institutes of Health Research.
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