Department of Intensive Care Unit, Xuzhou Cancer Hospital, Jiangsu Province, 221000, China.
Department of Intensive Care Unit, Xuzhou Cancer Hospital, Jiangsu Province, 221000, China.
Biochem Biophys Res Commun. 2020 Dec 17;533(4):1419-1426. doi: 10.1016/j.bbrc.2020.08.109. Epub 2020 Oct 21.
Inflammation has an essential role in regulating the pathogenesis of acute respiratory distress syndrome (ARDS). The serine/threonine kinase PIM2 is highly expressed in human macrophages, and exhibits regulatory role in inflammatory response. However, its effect on ARDS progression has not been investigated and still remains unclear. In the study, we attempted to investigate the potential of PIM2 during ARDS progression, and to reveal the underlying molecular mechanisms. Here, we found that PIM2 expression was dramatically up-regulated in lipopolysaccharide (LPS)-exposed murine macrophages through a dose- and time-dependent manner. Additionally, we found that PIM2 knockdown greatly alleviated LPS-triggered activation of Caspase-1, interleukin (IL)-1β, NOD-like receptor pyrin domain 3 (NLRP3) and apoptosis-associated speck-like protein (ASC) in macrophages, along with suppressed inflammatory response. Importantly, we identified that PIM2 could directly interact with NLRP3. PIM2 over-expression could further promote LPS-triggered inflammation and NLRP3 inflammasome in macrophages. Furthermore, PIM2 knockout significantly alleviated the severity of ARDS in LPS-challenged mice. Evidently decreased inflammatory response and NLRP3 inflammasome were detected in pulmonary tissues of LPS-treated mice with PIM2 deficiency. Together, our findings demonstrated that PIM2 as a promising therapeutic target for ARDS treatment through regulating NLRP3 inflammasome.
炎症在调节急性呼吸窘迫综合征（ARDS）的发病机制中起着重要作用。丝氨酸/苏氨酸激酶 PIM2 在人巨噬细胞中高度表达，并在炎症反应中发挥调节作用。然而，其对 ARDS 进展的影响尚未得到研究，仍不清楚。在这项研究中，我们试图研究 PIM2 在 ARDS 进展中的潜在作用，并揭示其潜在的分子机制。在这里，我们发现 PIM2 的表达在脂多糖（LPS）暴露的小鼠巨噬细胞中通过剂量和时间依赖性方式显著上调。此外，我们发现 PIM2 敲低可显著减轻 LPS 触发的巨噬细胞中 Caspase-1、白细胞介素（IL）-1β、NOD 样受体 pyrin 结构域 3（NLRP3）和凋亡相关斑点样蛋白（ASC）的激活，同时抑制炎症反应。重要的是，我们确定 PIM2 可以直接与 NLRP3 相互作用。PIM2 的过表达可进一步促进 LPS 触发的巨噬细胞炎症和 NLRP3 炎性体。此外，PIM2 敲除可显著减轻 LPS 诱导的小鼠 ARDS 的严重程度。在 LPS 处理的小鼠中，PIM2 缺乏时，肺部组织中炎症反应和 NLRP3 炎性体明显减轻。总之，我们的研究结果表明，PIM2 可作为治疗 ARDS 的有前途的治疗靶点，通过调节 NLRP3 炎性体。
