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The P2Y12 antagonist ticagrelor attenuates plasma cell and macrophage inflammatory responses in systemic lupus
Jingjing Lin1, Jiayuan Lai1, Jiaxiang Xu1
1Department of Pharmacy, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; School of Pharmacy, Fujian Medical University, Fuzhou 350004, China.
Background:
Persistent plasma cell responses in systemic lupus erythematosus (SLE) sustain autoantibody production and immune complex formation, contributing to macrophage activation and renal inflammation. We investigated P2Y12 expression in plasma cell-related populations and evaluated the effects of ticagrelor on humoral and macrophage inflammatory responses in SLE.
Methods:
P2Y12 expression was examined in peripheral blood mononuclear cells from patients with SLE and healthy controls and in renal tissues from patients with lupus nephritis. Functional studies were performed in SLE PBMCs, splenic B cells from MRL/lpr mice, bone marrow-derived macrophages, and RAW264.7 cells. CXCL12-directed migration, RNA sequencing, P2ry12 silencing, and macrophage stimulation with OVA-containing immune complexes or MRL/lpr serum were used to examine cellular responses. The effects of ticagrelor were further evaluated in vivo in MRL/lpr mice.
Results:
Patients with SLE showed increased frequencies of circulating plasma cells, together with increased P2Y12 expression in plasma cells and antibody-secreting cells (ASCs). Plasma-cell P2Y12 expression was positively correlated with CXCR4 expression. Renal tissues from patients with lupus nephritis showed stronger P2Y12, IgG, and C3 signals. In SLE PBMC cultures, ticagrelor attenuated plasma cell and ASC responses, accompanied by lower BLIMP1 and BATF expression and reduced BTK/SYK phosphorylation. Ticagrelor also reduced CXCL12-directed migration of bone marrow B-lineage cells and plasma cells. In MRL/lpr splenic B cells, ticagrelor altered ATP-associated transcriptional responses involving immune activation and inflammatory pathways. In macrophages, ticagrelor attenuated inflammatory responses to OVA-containing immune complexes, LPS, and MRL/lpr serum, while P2ry12 silencing altered macrophage inflammatory phenotypes in the presence of ticagrelor. In vivo, ticagrelor reduced circulating immunoglobulin and autoantibody levels, splenic B-cell abnormalities, renal IgG and C3 deposition, macrophage-associated inflammatory changes, and renal histopathological injury in MRL/lpr mice.
Conclusions:
P2Y12 expression was associated with plasma cell-related abnormalities in SLE, and ticagrelor attenuated humoral and macrophage inflammatory responses in both cellular and lupus-prone mouse models. These findings suggest that P2Y12-related immune regulation and the immunomodulatory actions of ticagrelor merit further investigation in SLE.
