Sepsis is an inflammatory disease characterized by dysregulation of inflammation. Macrophage-mediated inflammation has been implicated in the pathophysiology of sepsis. Itaconate is a metabolite produced in activated macrophages which has anti-inflammatory activities. In the present study, we investigated the potential effects of a cell-permeable itaconate derivative dimethyl itaconate on inflammation in sepsis. We established a lipopolysaccharide (LPS)-induced septic mouse model and administered dimethyl itaconate to the septic mice. The survival rate, serum level of pro-inflammatory cytokines, and lung pathology were evaluated. We also administered dimethyl itaconate to LPS-treated bone marrow–derived macrophages (BMDMs), and measured the cytokine production and Nrf2 expression. We also evaluated the effects of dimethyl itaconate on Nrf2-deficient mice. Administration of dimethyl itaconate enhanced survival rate, decreased serum level of TNF-α and IL-6, and ameliorated lung injury in septic mice. Dimethyl itaconate also suppressed LPS-induced production of TNF-α, IL-6, and NOS2 in BMDMs. Dimethyl itaconate activated Nrf2 and promoted the expression of Nrf2 and its downstream factor HO-1 and NQO-1. The regulatory activities of dimethyl itaconate on inflammatory cytokine production, mouse survival rate were abolished in septic Nrf2^−/− mice. Dimethyl itaconate suppressed the inflammatory responses of macrophages in sepsis.

脓毒症是一种炎症性疾病，其特征是炎症失调。巨噬细胞介导的炎症与败血症的病理生理学有关。衣康酸盐是活化巨噬细胞产生的代谢物，具有抗炎活性。在本研究中，我们研究了可渗透细胞的衣康酸酯衍生物衣康酸二甲酯对脓毒症炎症的潜在影响。我们建立了脂多糖 (LPS) 诱导的脓毒症小鼠模型，并向脓毒症小鼠施用衣康酸二甲酯。评估存活率、促炎细胞因子的血清水平和肺病理。我们还向 LPS 处理的骨髓源性巨噬细胞 (BMDM) 施用衣康酸二甲酯，并测量了细胞因子的产生和 Nrf2 的表达。我们还评估了衣康酸二甲酯对 Nrf2 缺陷小鼠的影响。衣康酸二甲酯的给药可提高败血症小鼠的存活率，降低血清 TNF-α 和 IL-6 水平，并改善肺损伤。衣康酸二甲酯还抑制了 LPS 诱导的 BMDM 中 TNF-α、IL-6 和 NOS2 的产生。衣康酸二甲酯激活 Nrf2 并促进 Nrf2 及其下游因子 HO-1 和 NQO-1 的表达。衣康酸二甲酯对炎性细胞因子产生、小鼠存活率的调节活性在脓毒症 Nrf2 中被消除 衣康酸二甲酯激活 Nrf2 并促进 Nrf2 及其下游因子 HO-1 和 NQO-1 的表达。衣康酸二甲酯对炎性细胞因子产生、小鼠存活率的调节活性在脓毒症 Nrf2 中被消除 衣康酸二甲酯激活 Nrf2 并促进 Nrf2 及其下游因子 HO-1 和 NQO-1 的表达。衣康酸二甲酯对炎性细胞因子产生、小鼠存活率的调节活性在脓毒症 Nrf2 中被消除^-/-小鼠。衣康酸二甲酯抑制脓毒症中巨噬细胞的炎症反应。