Sepsis is an acute systemic inflammatory disease triggered by bacterial infection leading organ dysfunctions that macrophages are responsible for major triggering of systemic inflammation. Treatment options are limited to antibiotics and drugs to manage the symptoms of sepsis, but there are currently no molecular-targeted therapies. Here, we identified a novel macrophage-preferable delivery peptide, C10, which we conjugated to truncated domains of NLRX1 (leucine-rich repeat region (LRR), and nucleotide binding domain (NBD)) to obtain C10-LRR and C10-NBD. Leucine rich amino acid of C10 enables macrophage preferable moieties that efficiently deliver a cargo protein into macrophages in vitro and in vivo. C10-LRR but not C10-NBD significantly improved survival in an LPS-mediated lethal endotoxemia sepsis model. C10-LRR efficiently inhibited IL-6 production in peritoneal macrophages via prevention of IκB degradation and p65 phosphorylation. In addition, C10-LRR negatively regulated IL-1β production by preventing caspase-1 activation with a sustained mitochondrial MAVS level. Finally, co-treatment with anti-TNFα antibody and C10-LRR had a synergistic effect in an LPS-induced sepsis model. Collectively, these findings indicate that C10-LRR could be an effective therapeutic agent to treat systemic inflammation in sepsis by regulating both NF-κB and inflammasome signaling activation.

脓毒症是一种由细菌感染引发的急性全身性炎症性疾病，导致器官功能障碍，巨噬细胞负责主要引发全身性炎症。治疗选择仅限于抗生素和治疗败血症症状的药物，但目前还没有分子靶向疗法。在这里，我们鉴定了一种新的巨噬细胞首选递送肽 C10，我们将其与 NLRX1 的截短结构域（富含亮氨酸的重复区域 (LRR) 和核苷酸结合结构域 (NBD)）缀合以获得 C10-LRR 和 C10-NBD。C10 的富含亮氨酸的氨基酸使巨噬细胞优选的部分能够在体外和体内有效地将货物蛋白递送到巨噬细胞中. 在 LPS 介导的致死性内毒素血症脓毒症模型中，C10-LRR 而不是 C10-NBD 显着提高了存活率。C10-LRR 通过阻止 IκB 降解和 p65 磷酸化有效抑制腹腔巨噬细胞中 IL-6 的产生。此外，C10-LRR 通过在持续的线粒体 MAVS水平上阻止 caspase-1 活化来负调节 IL-1β 的产生。最后，用抗 TNFα 抗体和 C10-LRR 共同治疗在 LPS 诱导的脓毒症模型中具有协同作用。总的来说，这些发现表明 C10-LRR 可能是一种通过调节 NF-κB 和炎性体信号激活来治疗脓毒症全身炎症的有效治疗剂。