Leucine rich alpha-2-glycoprotein 1 (Lrg1) silencing protects against sepsis-mediated brain injury by inhibiting transforming growth factor beta1 (TGFβ1)/SMAD signaling pathway

• Published in: Bioengineered 2022-03, Vol.13 (3), p.7316-7327
• Main Authors: Miao, Youhan, Wang, Meihua, Cai, Xiaojuan, Zhu, Qiqi, Mao, Liping
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; behavioral change; Brain Injuries; Glycoproteins - genetics; Glycoproteins - metabolism; Inflammation; inflammatory response; Leucine; Lipopolysaccharides; lrg1; Mice; Research Paper; Sepsis - complications; Sepsis - genetics; Sepsis-associated encephalopathy; Signal Transduction; TGFβ1/SMAD signaling; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 2165-5979; 2165-5987
• DOI: 10.1080/21655979.2022.2048775

Sepsis-associated encephalopathy (SAE) is key manifestation of sepsis which is responsible for increased morbidity and mortality. Leucine rich alpha-2-glycoprotein 1 (Lrg1) is a secreted protein implicated in a variety of diseases. We aimed to explore the effects and potential mechanism of Lrg1 on sepsis-mediated brain injury. A sepsis-induced brain damage mice model was established. Then, ELISA was utilized to detect the levels of inflammatory factors in brain tissues. Behavioral performance, spatial learning and memory of mice were evaluated by open field test and Morris water maze test. The number of neurons was tested by H&E staining. Lrg1 expression was evaluated by RT-qPCR and western blot. In vitro, mouse hippocampal neuronal cell line (HT22) was stimulated by lipopolysaccharide (LPS). After Lrg1 silencing, cell viability was determined using CCK-8 and cell apoptosis was assessed by TUNEL. The levels of inflammatory factors were detected by ELISA. Moreover, western blot was applied to analyze the expression of proteins in transforming growth factor beta1 (TGFβ1)/SMAD signaling. Results revealed that mice in the model group showed obvious behavioral changes. Lrg1 was highly expressed in the brain tissues of model mice. Besides, Lrg1 knockdown suppressed the inflammation and apoptosis of LPS-induced HT22 cells. Moreover, Lrg1 silencing caused the inactivation of TGFβ1/SMAD signaling. Rescue assays confirmed that TGFβ1 overexpression reversed the impacts of Lrg1 deletion on the inflammation and apoptosis in LPS-induced HT22 cells. Collectively, Lrg1 silencing alleviates brain injury in SAE via inhibiting TGFβ1/SMAD signaling, implying that Lrg1 might serve as a promising target for SAE treatment.