Luo Man, Hu Lijuan, Li Dandan, Wang Yanying, He Yuting, Zhu Lei, Ren Weiying
Department of Geriatric, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China.
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China.
Mol Immunol. 2017 Oct;90:1-10. doi: 10.1016/j.molimm.2017.06.035. Epub 2017 Jun 24.
Myeloid differentiation protein 2 (MD-2) is required in the recognition of lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and participates in LPS-induced alveolar macrophage (AM) inflammation during acute lung injury (ALI). Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome aggravates inflammation in LPS-induced ALI. However, there is currently little known about the relationship between MD-2 signaling and the NLRP3 inflammasome. This study showed that NLRP3 expression, IL-1beta (IL-1β) secretion, and pyroptosis were up-regulated after LPS stimulation in the NR8383 AM cell-line. MD-2 gene knock-down reduced LPS-induced mRNA and protein expression of NLRP3 and IL-1β secretion in NR8383 cells, and inhibited the MyD88/NF-κB signaling pathway. Conversely, over-expression of MD-2 not only heightened NLRP3, MyD88, and NF-κB p65 protein expression, it also aggravated the LPS-induced inflammatory response. Furthermore, the NF-κB inhibitor SN50 had a beneficial role in decreasing NLRP3 and caspase-1 mRNA and protein expression. The observations suggest that MD-2 helps to regulate LPS-induced NLRP3 inflammasome activation and the inflammatory response in NR8383 cells, and likely does so by affecting MyD88/NF-κB signaling.
髓样分化蛋白2（MD-2）是Toll样受体4（TLR4）识别脂多糖（LPS）所必需的，并且在急性肺损伤（ALI）期间参与LPS诱导的肺泡巨噬细胞（AM）炎症反应。含NOD样受体家族吡啶结构域3（NLRP3）炎性小体的激活会加重LPS诱导的ALI中的炎症反应。然而，目前关于MD-2信号与NLRP3炎性小体之间的关系知之甚少。本研究表明，在NR8383 AM细胞系中，LPS刺激后NLRP3表达、白细胞介素-1β（IL-1β）分泌和细胞焦亡上调。MD-2基因敲低降低了LPS诱导的NR8383细胞中NLRP3的mRNA和蛋白表达以及IL-1β分泌，并抑制了MyD88/NF-κB信号通路。相反，MD-2的过表达不仅提高了NLRP3、MyD88和NF-κB p65蛋白的表达，还加重了LPS诱导的炎症反应。此外，NF-κB抑制剂SN50在降低NLRP3和半胱天冬酶-1的mRNA和蛋白表达方面具有有益作用。这些观察结果表明，MD-2有助于调节LPS诱导的NR8383细胞中NLRP3炎性小体的激活和炎症反应，并且可能是通过影响MyD88/NF-κB信号通路来实现的。
