Xu Wen, Wu Cheng-Jun, Jiao Yan-Mei, Mei Xiao-Le, Huang Lei, Qin En-Qiang, Tu Bo, Zhao Peng, Wang Li-Feng, Chen Wei-Wei
Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
IC Technology Key Lab of Liaoning, School of Biomedical Engineering, Dalian University of Technology, Dalian, China.
Front Microbiol. 2022 Jul 7;13:923215. doi: 10.3389/fmicb.2022.923215. eCollection 2022.
Human adenovirus (HAdV) infection causes excessive inflammation associated with severe tissue injury, such as pneumonia. The molecules involved in the underlying inflammatory mechanisms remain to be elucidated. Receptor for advanced glycation end product (RAGE) is mainly expressed on immune cells and lung tissues, and it is a key factor in the initiation and development of inflammation. RAGE can be cleaved by metalloprotease 9 (MMP9) to release the extracellular segment, which is named soluble RAGE (sRAGE), into the intercellular space, where it can bind to RAGE ligands and block RAGE activation and subsequent inflammation. In our study, we enrolled HAdV-infected patients and their contacts to examine the relationship between sRAGE and inflammation induced by HAdV infection. The results showed that HAdV infection stimulated inflammatory cytokine secretion, increased such as high mobility group box 1 (HMGB1) levels, and suppressed sRAGE expression. sRAGE levels were significantly different between patients with or without pneumonia. We also found that MMP9 was significantly lower in patients with pneumonia, and it was positively correlated with sRAGE levels over 7 days after disease onset. The mitogen-activated protein kinase (MAPK) pathway is an important immune activation signaling pathway that is regulated by RAGE. We observed the activation of the MAPK pathway in the peripheral blood mononuclear cells (PBMCs) of patients. Negative correlations between sRAGE and phosphorylated JNK and p38 were observed. These results suggest that sRAGE is involved in HAdV-induced inflammatory responses, and might be a potential therapeutic target to alleviate the HAdV-induced excessive inflammation.
人腺病毒（HAdV）感染会引发与严重组织损伤相关的过度炎症，如肺炎。潜在炎症机制中涉及的分子仍有待阐明。晚期糖基化终产物受体（RAGE）主要在免疫细胞和肺组织上表达，是炎症发生和发展的关键因素。RAGE可被金属蛋白酶9（MMP9）切割，释放细胞外片段，即可溶性RAGE（sRAGE）进入细胞间隙，在那里它可以与RAGE配体结合，阻断RAGE激活及后续炎症反应。在我们的研究中，我们招募了HAdV感染患者及其接触者，以研究sRAGE与HAdV感染诱导的炎症之间的关系。结果显示，HAdV感染刺激炎症细胞因子分泌，增加如高迁移率族蛋白B1（HMGB1）水平，并抑制sRAGE表达。有肺炎和无肺炎患者的sRAGE水平存在显著差异。我们还发现，肺炎患者的MMP9显著降低，且在疾病发作后7天内其与sRAGE水平呈正相关。丝裂原活化蛋白激酶（MAPK）途径是一条由RAGE调节的重要免疫激活信号通路。我们观察到患者外周血单核细胞（PBMCs）中MAPK途径的激活。观察到sRAGE与磷酸化JNK和p38之间呈负相关。这些结果表明，sRAGE参与了HAdV诱导的炎症反应，可能是减轻HAdV诱导的过度炎症的潜在治疗靶点。
