系统性红斑狼疮
促炎细胞因子
免疫系统
免疫学
医学
炎症
CD8型
获得性免疫系统
HMGB1
树突状细胞
髓样
自身抗体
脾细胞
FOXP3型
T细胞
内分泌学
内科学
抗体
疾病
作者
Luz P. Blanco,Eduardo Patiño-Martínez,Shuichiro Nakabo,Mingzeng Zhang,Hege Lynum Pedersen,Xinghao Wang,Carmelo Carmona‐Rivera,Dillon Claybaugh,Zu‐Xi Yu,Equar Desta,Mariana J. Kaplan
摘要
Itaconic acid, a Krebs cycle-derived immunometabolite, is synthesized by myeloid cells in response to danger signals to control inflammasome activation, type I interferon (IFN) responses, and oxidative stress. As these pathways are dysregulated in systemic lupus erythematosus (SLE), we investigated the role of an itaconic acid derivative in the treatment of established murine lupus.Female (NZW × NZB)F1 lupus-prone mice were administered 4-octyl itaconate (4-OI) or vehicle starting after clinical onset of disease (30 weeks of age) for 4 weeks (n = 10 mice /group). At 34 weeks of age (peak disease activity), animals were euthanized, organs and serum were collected, and clinical, metabolic, and immunologic parameters were evaluated.Proteinuria, kidney immune complex deposition, renal scores of severity and inflammation, and anti-RNP autoantibodies were significantly reduced in the 4-OI treatment group compared to the vehicle group. Splenomegaly decreased in the 4-OI group compared to vehicle, with decreases in activation markers in innate and adaptive immune cells, increases in CD8+ T cell numbers, and inhibition of JAK1 activation. Gene expression analysis in splenocytes showed significant decreases in type I IFN and proinflammatory cytokine genes and increased Treg cell-associated markers in the 4-OI group compared to the vehicle group. In human control and lupus myeloid cells, 4-OI in vitro treatment decreased proinflammatory responses and B cell responses.These results support targeting immunometabolism as a potentially viable approach in autoimmune disease treatment, with 4-OI displaying beneficial roles attenuating immune dysregulation and organ damage in lupus.
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