Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China.
Department of Anesthesiology, Kaifeng People's Hospital, Kaifeng 475000, China.
Biochem Pharmacol. 2021 Feb;184:114399. doi: 10.1016/j.bcp.2020.114399. Epub 2020 Dec 28.
Dedicator of cytokinesis 2 (DOCK2), an atypical Rac activator, has important anti-inflammatory properties in blepharitis, enteric bacterial infection and colitis. However, the roles of DOCK2 in macrophage activation and acute lung injury (ALI) are still poorly elucidated. In vitro studies demonstrated that DOCK2 was essential for the nucleotide-sensing Toll-like receptor (TLR) 4-mediated inflammatory response in macrophages. We also confirmed that exposure of macrophages to LPS induced Rac activation through a TLR4-independent, DOCK2-dependent mechanism. Phosphorylation of IκB kinase (IKK) β and nuclear translocation of transcription factor nuclear factor kappa B (NF-κB) were impaired in Ad-shDOCK2-expressing macrophages, resulting in a decreased inflammatory response. Similar results were obtained when EHop-016 (a Rac inhibitor) was used to treat uninfected macrophages. In summary, these data indicate that the DOCK2-Rac signaling pathway acts in parallel with TLR4 engagement to control IKKβ activation for inflammatory cytokine release. Next, we investigated whether pharmacological inhibition of DOCK2 protects against endotoxemia-induced lung injury in mice. Treatment with 4-[3'-(2″-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP), a small-molecule inhibitor of DOCK2, reduced the severity of lung injury, as indicated by decreases in the lung injury score and myeloperoxidase (MPO) activity. Moreover, CPYPP attenuated LPS-induced proinflammatory cytokine release in mice. Our studies suggest that inhibition of DOCK2 may suppress LPS-induced macrophage activation and that DOCK2 may be a novel target for treating endotoxemia-related ALI.
细胞分裂蛋白 2（DOCK2）是一种非典型 Rac 激活剂，在睑缘炎、肠内细菌感染和结肠炎中具有重要的抗炎特性。然而，DOCK2 在巨噬细胞激活和急性肺损伤（ALI）中的作用仍未得到充分阐明。体外研究表明，DOCK2 是巨噬细胞中核苷酸感应 Toll 样受体（TLR）4 介导的炎症反应所必需的。我们还证实，巨噬细胞暴露于 LPS 会通过 TLR4 非依赖性、DOCK2 依赖性机制诱导 Rac 激活。表达 Ad-shDOCK2 的巨噬细胞中 IκB 激酶（IKK）β的磷酸化和转录因子核因子 kappa B（NF-κB）的核转位受损，导致炎症反应减弱。当使用 EHop-016（一种 Rac 抑制剂）处理未感染的巨噬细胞时，也得到了类似的结果。总之，这些数据表明，DOCK2-Rac 信号通路与 TLR4 结合平行作用，以控制 IKKβ的激活，从而释放炎症细胞因子。接下来，我们研究了药理抑制 DOCK2 是否可以预防内毒素血症引起的小鼠肺损伤。用 4-[3'-(2″-氯苯基）-2′-丙烯-1′-亚基]-1-苯基-3,5-吡唑烷二酮（CPYPP）治疗，一种 DOCK2 的小分子抑制剂，降低了肺损伤评分和髓过氧化物酶（MPO）活性，表明肺损伤程度减轻。此外，CPYPP 减弱了 LPS 诱导的小鼠促炎细胞因子的释放。我们的研究表明，抑制 DOCK2 可能抑制 LPS 诱导的巨噬细胞激活，DOCK2 可能是治疗内毒素血症相关 ALI 的新靶点。
