Abstract:
A wide variety of electrophilic derivatives of itaconate, the Kreb\'s cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.
摘要:
各种各样的衣康酸酯亲电子衍生物,克雷布的循环代谢产物,是免疫调节的,然而,这些衍生品有重叠的,有时是相互矛盾的活动。因此,我们建立了一个遗传系统来研究人巨噬细胞中内源性产生的衣康酸酯的免疫调节功能。内源性衣康酸酯由抑制炎性细胞因子产生的多种先天信号驱动。内源性衣康酸酯直接靶向IRAK4中的半胱氨酸13(破坏IRAK4自磷酸化和活化),驱动核因子κB的降解,并调节全球泛素化模式。因此,细胞不能使衣康酸酯过度产生炎症细胞因子,如肿瘤坏死因子α(TNFα),白细胞介素-6(IL-6),和IL-1β对这些先天激活剂的反应。相比之下,干扰素(IFN)β的产生,LPS的下游,需要生产衣康酸。这些数据表明,衣康酸酯是多个先天信号通路下游炎性细胞因子产生的关键仲裁者,为开发用于治疗自身免疫的衣康酸模拟物奠定基础。