RNA-seq on platelets from mice with systemic lupus erythematosus and FcgammaRIIA (Fcgr2a) expression

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (IC) in organs and tissues. The expression of FcgammaRIIA by human platelets, which is their unique receptor for IgG antibodies, positions them to ideally respond to circulating IC. Whereas chronic platelet activation and thrombosis are well-recognized features of human SLE, the exact mechanisms underlying platelet activation in SLE are still unknown. Here, we evaluated the involvement of FcgammaRIIA in the course of SLE and platelet activation. In SLE patients, levels of IC are associated with platelet activation. As FcgammaRIIA is absent in mice and murine platelets do not respond to IC in any existing mouse model of SLE, we introduced the FcgammaRIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, FcgammaRIIA expression by bone-marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in FcgammaRIIAexpressing and non-expressing mice, but an enrichment for type-I interferon response gene changes was specifically observed in the FcgammaRIIA mice. Moreover, circulating platelet were degranulated and were found interacting with neutrophils in FcgammaRIIA expressing lupus mice. FcgammaRIIA expression in lupus mice also led to thrombosis in lungs and kidneys. The model recapitulates hallmarks of human SLE and can be utilized to identify contributions of different cellular lineages in the manifestations of SLE. The study further reveals a role for FcgammaRIIA in nephritis and in platelet activation in SLE.