Emergency Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Emergency Department, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
J Cell Mol Med. 2021 Feb;25(4):2013-2024. doi: 10.1111/jcmm.16082. Epub 2020 Dec 27.
Sepsis is a systemic inflammatory response to invading pathogens, leading to high mortality rates in intensive care units worldwide. Krüppel-like factor 4 (KLF4) is an important anti-inflammatory transcription factor. In this study, we investigate the anti-inflammatory role of KLF4 in caecal ligation and puncture (CLP)-induced septic mice and lipopolysaccharide (LPS)-induced RAW264.7 cells and its potential mechanism. We found that KLF4 was down-regulated in CLP-induced septic mice and in LPS-induced RAW264.7 cells, and that its overexpression led to increased survival rates of septic mice along with inhibited inflammatory response in vivo and in vitro. ITGA2B was up-regulated in the setting of sepsis and was inhibited by KLF4 overexpression. ITGA2B knock-down mimicked the effects of KLF4 overexpression on septic mice and LPS-induced RAW264.7 cells. TLR4 promoted the phosphorylation of ERK1/2 and then up-regulated the ubiquitination and the degradation of KLF4, thereby elevating the expression of ITGA2B. Moreover, TLR4 knock-down or treatment with PD98059 (a MEK inhibitor) inhibited inflammatory response in the setting of sepsis in vivo and in vitro. Furthermore, this effect of PD98059 treatment was lost upon KLF4 knock-down. Collectively, these results explain the down-regulation of KLF4 in sepsis, namely via TLR4 promotion of ERK1/2 phosphorylation, and identify ITGA2B as the downstream gene of KLF4, thus highlighting the anti-inflammatory role of KLF4 in sepsis.
脓毒症是一种全身炎症反应，由入侵病原体引起，导致全球重症监护病房的死亡率居高不下。Krüppel 样因子 4（KLF4）是一种重要的抗炎转录因子。在本研究中，我们研究了 KLF4 在盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠和脂多糖（LPS）诱导的 RAW264.7 细胞中的抗炎作用及其潜在机制。我们发现，KLF4 在 CLP 诱导的脓毒症小鼠和 LPS 诱导的 RAW264.7 细胞中表达下调，而过表达 KLF4 可提高脓毒症小鼠的存活率，并抑制体内和体外的炎症反应。ITGA2B 在脓毒症中上调，并被 KLF4 过表达抑制。ITGA2B 敲低模拟了 KLF4 过表达对脓毒症小鼠和 LPS 诱导的 RAW264.7 细胞的影响。TLR4 促进 ERK1/2 的磷酸化，进而上调 KLF4 的泛素化和降解，从而提高 ITGA2B 的表达。此外，TLR4 敲低或使用 PD98059（一种 MEK 抑制剂）抑制体内和体外脓毒症中的炎症反应。此外，KLF4 敲低消除了 PD98059 治疗的这种作用。综上所述，这些结果解释了脓毒症中 KLF4 的下调，即通过 TLR4 促进 ERK1/2 的磷酸化，确定 ITGA2B 为 KLF4 的下游基因，从而突出了 KLF4 在脓毒症中的抗炎作用。
