Sepsis-induced organ damage is caused by systemic inflammatory response syndrome (SIRS), which results in substantial comorbidities. Therefore, it is of medical importance to identify molecular brakes that can be exploited to dampen inflammation and prevent the development of SIRS. We investigated the role of phosphatase and tensin homolog (PTEN) in suppressing SIRS, increasing microbial clearance, and preventing lung damage. Septic patients and mice with sepsis exhibited increased PTEN expression in leukocytes. Myeloid-specific Pten deletion in an animal model of sepsis increased bacterial loads and cytokine production, which depended on enhanced myeloid differentiation primary response gene 88 (MyD88) abundance and resulted in mortality. PTEN-mediated induction of the microRNAs (miRNAs) miR125b and miR203b reduced the abundance of MyD88. Loss- and gain-of-function assays demonstrated that PTEN induced miRNA production by associating with and facilitating the nuclear localization of Drosha-Dgcr8, part of the miRNA-processing complex. Reconstitution of PTEN-deficient mouse embryonic fibroblasts with a mutant form of PTEN that does not localize to the nucleus resulted in retention of Drosha-Dgcr8 in the cytoplasm and impaired production of mature miRNAs. Thus, we identified a regulatory pathway involving nuclear PTEN–mediated miRNA generation that limits the production of MyD88 and thereby limits sepsis-associated mortality.

败血症诱导的器官损害是由全身性炎症反应综合征（SIRS）引起的，其导致大量合并症。因此，鉴定可用于减轻炎症和预防SIRS发生的分子制动器具有医学重要性。我们调查了磷酸酶和张力蛋白同系物（PTEN）在抑制SIRS，增加微生物清除率和预防肺部损伤中的作用。败血症的败血症患者和小鼠在白细胞中表现出PTEN表达增加。髓样特异性Pten败血症动物模型中的缺失会增加细菌负荷和细胞因子的产生，这取决于增强的髓样分化初级反应基因88（MyD88）的丰度并导致死亡。PTEN介导的microRNA（miRNA）miR125b和miR203b的诱导减少了MyD88的丰度。功能丧失和功能增强试验表明，PTEN通过与Drosha-Dgcr8（miRNA加工复合物的一部分）相关联并促进其核定位而诱导了miRNA的产生。用不位于细胞核的PTEN突变形式重建PTEN缺陷型小鼠胚胎成纤维细胞会导致Drosha-Dgcr8保留在细胞质中，并损害成熟miRNA的产生。因此，