乌头脱羧酶 1/itaconate 通路调节免疫失调,并与系统性红斑狼疮的心血管疾病标志物有关。

Eduardo Patino Martinez, Shuichiro Nakabo, Kan Jiang, Carmelo Carmona- Rivera, Wanxia Li Tsai, Dillon Claybaugh, Zu-Xi Yu, Aracely Romero, Eric Bohrnsen, Benjamin Schwarz, Miguel A. Solis Barbosa, Luz P. Blanco, Mohammad Naqi, Yenealem Temesgen-Oyelakim, Michael Davis, Nehal Mehta, Faiza Naz, Stephen Brooks, Stefania dell Orso, Sarfaraz Hasni, Mariana J. Kaplan
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Methods\nWe characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ). Wild type and Acod1-/- mice were exposed to topical IMQ for 5 weeks to induce an SLE phenotype and immune dysregulation was quantified. Itaconate serum levels were quantified in SLE patients and associated to cardiometabolic parameters and disease activity. Results\nACOD1 was induced in mouse bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages following in vitro TLR7 stimulation. This induction was partially dependent on type I Interferon receptor signaling and specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum anti-dsDNA and proinflammatory cytokine levels, enhanced kidney immune complex deposition and proteinuria, when compared to the IMQ-treated WT mice. 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摘要

摘要目的 克雷布斯循环酶中的姜酸脱羧酶1(ACOD1)在髓样细胞中介导伊它康酸的合成。以前,我们曾报道过给小鼠注射伊他康酸 4-辛酯可减轻狼疮表型。在此,我们探讨了内源性 ACOD1/衣康酸通路在小鼠狼疮发病中的作用,以及它们在系统性红斑狼疮过早心血管损伤中的相关性。方法我们研究了TLR7激动剂(咪喹莫特,IMQ)作用下骨髓源性巨噬细胞和人类单核细胞源性巨噬细胞中Acod1蛋白表达的特征。将野生型小鼠和 Acod1-/- 小鼠暴露于局部 IMQ 5 周,以诱导系统性红斑狼疮表型,并对免疫失调进行量化。对系统性红斑狼疮患者的伊塔康酸血清水平进行量化,并将其与心脏代谢参数和疾病活动联系起来。结果 在体外 TLR7 刺激下,小鼠骨髓衍生巨噬细胞(BMDM)和人类单核细胞衍生巨噬细胞诱导了 ACOD1。这种诱导部分依赖于 I 型干扰素受体信号传导和特定的细胞内通路。在 IMQ 诱导的红斑狼疮小鼠模型中,与 IMQ 处理的 WT 小鼠相比,ACOD1 基因敲除(Acod1-/-)小鼠显示出脾脏结构破坏、血清抗dsDNA 和促炎细胞因子水平升高、肾脏免疫复合物沉积增强和蛋白尿。与这些结果一致的是,暴露于 IMQ 的 Acod1-/- BMDM 在体外表现出更高的促炎特征。与健康对照血清相比,系统性红斑狼疮血清中的伊他康酸水平降低,这与特定的心脏代谢参数紊乱和亚临床血管疾病有关。结论这些研究结果表明,ACOD1/伊塔康酸通路在系统性红斑狼疮中发挥着重要的免疫调节和血管保护作用,支持伊塔康酸类似物在自身免疫性疾病中的潜在治疗作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers in SLE.
Abstract Objective The Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in myeloid cells.. Previously, we reported that administration of 4-octyl itaconate abrogated lupus phenotype in mice. Here, we explore the role of the endogenous ACOD1/itaconate pathway in the development of murine lupus as well as their relevance in premature cardiovascular damage in SLE. Methods We characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ). Wild type and Acod1-/- mice were exposed to topical IMQ for 5 weeks to induce an SLE phenotype and immune dysregulation was quantified. Itaconate serum levels were quantified in SLE patients and associated to cardiometabolic parameters and disease activity. Results ACOD1 was induced in mouse bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages following in vitro TLR7 stimulation. This induction was partially dependent on type I Interferon receptor signaling and specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum anti-dsDNA and proinflammatory cytokine levels, enhanced kidney immune complex deposition and proteinuria, when compared to the IMQ-treated WT mice. Consistent with these results, Acod1-/- BMDM exposed to IMQ showed higher proinflammatory features in vitro. Itaconate levels were decreased in SLE serum compared to healthy control sera, in association with specific perturbed cardiometabolic parameters and subclinical vascular disease. Conclusion These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in SLE, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.
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