Background The accumulation of DNA and nuclear components in blood and their recognition by autoantibodies play a central role in the pathophysiology of systemic lupus erythematosus (SLE). Despite the efforts, the sources of these circulating autoantigens in SLE are still unclear. While damaged organs and activated cells are generally considered as potential sources of autoantigens, platelets are often overlooked given that they are anucleated and thereby cannot release genomic DNA. However, accumulating findings suggest that mitochondria are also targeted by antibodies in SLE.
Methods We examined the presence of extracellular mitochondria in blood of patients with SLE and determined correlations with platelet activation. Because mice lack FcγRIIA and murine platelets are completely devoid of receptor capable of binding IgG-containing immune complexes, we generated transgenic lupus mice expressing FcγRIIA for our in vivo investigations. We used a reporter mouse with red fluorescent protein targeted to the mitochondrion to identify the cellular source of the extracellular mitochondria.
Results We found extracellular mitochondrial DNA (mtDNA) and mitochondrial organelles in the plasma of patients with SLE. The concentrations of mtDNA and extracellular mitochondria were higher than in healthy individuals, and mtDNA levels correlated with that of platelet factor 4 (PF4), a marker of platelet degranulation. The majority of the detected mtDNA was associated with the extracellular mitochondrial organelle. In our in vitro and in vivo investigations, mitochondrial release by platelets required the stimulation of platelet FcγRIIA, a receptor for immune complexes. FcγRIIA expression in lupus-prone mice accelerated nephritis, led to the recruitment of platelets in kidneys and to the release of mitochondria in vivo. Using our mouse model with fluorescently labeled mitochondria, we confirmed platelets as a source of extracellular mitochondria driven by FcγRIIA and its co-signaling by the fibrinogen receptor α2bβ3 in vivo.
Conclusion Our findings suggest that platelets might be a key source of mitochondrial antigens in SLE and might be a therapeutic target for treating SLE.
Acknowledgments This work was supported by a Foundation grant from the Canadian Institutes of Health Research (CIHR) (to E.B.). E.B. is recipient of a new investigator award from the CIHR and the Fonds de Recherche en Santé du Quebec (FRQS) PRF is recipient of a tier 1 Canada Research Chair on Systemic Autoimmune Rheumatic Diseases.
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