Sepsis‐induced myocardial dysfunction (SIMD), a deadly symptom in sepsis patients, is mainly caused by cardiovascular inflammation. However, it remains unclear how systemic inflammation triggers and aggravates cardiovascular inflammation in the pathogenesis of SIMD. This study found that proinflammatory cytokines and H₂O₂ concentrations were significantly induced in SIMD‐mice. In particular, a microarray analysis of CD63⁺ exosomes isolated from sham‐ and SIMD‐monocytes revealed a significant induction of thioredoxin‐interacting protein (TXNIP) and NLR family pyrin domain‐containing 3 (NLRP3). We proved that oxidative stress caused the disassociation of the TXNIP‐TRX2 (thioredoxin 2) complex and the assembly of the TXNIP‐NLRP3 complex. In addition, this finding showed that the latter complex could be embedded into CD63⁺ exosomes and traffic from monocytes to the resident heart macrophages, where it activated caspase‐1 and cleaved inactive interleukin 1β (IL‐1β) and IL‐18. Furthermore, using an amplified luminescent proximity homogeneous assay (Alpha) with GST‐TXNIP and His‐NLRP3, we obtained a small molecule named PSSM1443 that could disrupt the TXNIP‐NLRP3 interaction in vitro, impairing NLRP3 downstream events. Of note, after administering PSSM1443 to the SIMD‐mice, we found the small molecule could significantly suppress the activation of caspase‐1 and the cleavage of pro‐IL‐1β and pro‐IL‐18, reducing inflammation in the SIMD‐mice. Collectively, our results reveal that monocyte‐derived exosomes harbor the overexpressed TXNIP‐NLRP3 complex, which traffics from circulating monocytes to local macrophages and promotes the cleavage of inactive IL‐1β and IL‐18 in the macrophages, aggravating cardiovascular inflammation. PSSM1443 functions as an inhibitor of the TXNIP‐NLRP3 complex and its administration can decrease inflammation in SIMD‐mice.

中文翻译：

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靶向 TXNIP-NLRP3 与 PSSM1443 的相互作用以抑制脓毒症诱导的心肌功能障碍的炎症

脓毒症诱导的心肌功能障碍（SIMD）是脓毒症患者的一种致命症状，主要由心血管炎症引起。然而，目前尚不清楚全身炎症如何在 SIMD 的发病机制中触发和加重心血管炎症。该研究发现，在 SIMD 小鼠中显着诱导了促炎细胞因子和 H ₂ O ₂浓度。特别是，对从假单核细胞和 SIMD 单核细胞中分离的 CD63 ⁺外泌体的微阵列分析揭示了硫氧还蛋白相互作用蛋白 ( TXNIP ) 和 NLR 家族含 pyrin 结构域 3 ( NLRP3）。我们证明氧化应激导致 TXNIP-TRX2（硫氧还蛋白 2）复合物的解离和 TXNIP-NLRP3 复合物的组装。此外，这一发现表明后一种复合物可以嵌入 CD63 ⁺外泌体和从单核细胞到常驻心脏巨噬细胞的运输，在那里它激活 caspase-1 并切割无活性的白细胞介素 1β (IL-1β) 和 IL-18。此外，使用具有 GST-TXNIP 和 His-NLRP3 的放大发光邻近均相测定 (Alpha)，我们获得了一种名为 PSSM1443 的小分子，它可以在体外破坏 TXNIP-NLRP3 相互作用，从而损害 NLRP3 下游事件。值得注意的是，在对 SIMD 小鼠施用 PSSM1443 后，我们发现该小分子可以显着抑制 caspase-1 的激活以及 pro-IL-1β 和 pro-IL-18 的裂解，从而减轻 SIMD 小鼠的炎症。总的来说，我们的结果表明单核细胞衍生的外泌体含有过表达的 TXNIP-NLRP3 复合物，它从循环单核细胞运输到局部巨噬细胞并促进巨噬细胞中无活性的 IL-1β 和 IL-18 的裂解，加剧心血管炎症。PSSM1443 作为 TXNIP-NLRP3 复合物的抑制剂，其给药可以减少 SIMD 小鼠的炎症。