Abstract：
The ovarian tumor (OTU) family consists of deubiquitinating enzymes thought to play a crucial role in immunity. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) pose substantial clinical challenges due to severe respiratory complications and high mortality resulting from uncontrolled inflammation. Despite this, no study has explored the potential link between the OTU family and ALI/ARDS. Using publicly available high-throughput data, 14 OTUs were screened in a simulating bacteria- or LPS-induced ALI model. Subsequently, gene knockout mice and transcriptome sequencing were employed to explore the roles and mechanisms of the selected OTUs in ALI. Our screen identified OTUD1 in the OTU family as a deubiquitinase highly related to ALI. In the LPS-induced ALI model, deficiency of OTUD1 significantly ameliorated pulmonary edema, reduced permeability damage, and decreased lung immunocyte infiltration. Furthermore, RNA-seq analysis revealed that OTUD1 deficiency inhibited key pathways, including the IFN-γ/STAT1 and TNF-α/NF-κB axes, ultimately mitigating the severity of immune responses in ALI. In summary, our study highlights OTUD1 as a critical immunomodulatory factor in acute inflammation. These findings suggest that targeting OTUD1 could hold promise for the development of novel treatments against ALI/ARDS.
摘要：
卵巢肿瘤（OTU）家族由去泛素化酶组成，被认为在免疫中起关键作用。急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）由于严重的呼吸系统并发症和由不受控制的炎症引起的高死亡率而带来了巨大的临床挑战。尽管如此,尚无研究探讨OTU家族与ALI/ARDS之间的潜在联系.使用公开可用的高通量数据，在模拟细菌或LPS诱导的ALI模型中筛选14个OTU。随后，通过基因敲除小鼠和转录组测序，探讨了选定的OTU在ALI中的作用和机制。我们的筛选将OTU家族中的OTUD1鉴定为与ALI高度相关的去泛素酶。在LPS诱导的ALI模型中,OTUD1缺乏可显着改善肺水肿，减少渗透性损害，肺免疫细胞浸润减少。此外，RNA-seq分析显示OTUD1缺陷抑制了关键途径，包括IFN-γ/STAT1和TNF-α/NF-κB轴，最终减轻ALI中免疫反应的严重程度。总之,我们的研究强调OTUD1是急性炎症中的关键免疫调节因子.这些发现表明，靶向OTUD1可能有望开发针对ALI/ARDS的新型治疗方法。
