Loss of RAGE prevents chronic intermittent hypoxia-induced nonalcoholic fatty liver disease via blockade of NF-кB pathway.

In recent years, receptor for advanced glycation end-products (RAGE) has been documented to induce liver fibrosis and inflammatory reaction. Further, microarray data analysis of this study predicted high expression of RAGE in non-alcoholic fatty liver disease (NAFLD). However, its specific mechanisms remain to be elucidated. Hence, this study is aimed at investigating the mechanistic insights of RAGE in chronic intermittent hypoxia (CIH)-induced NAFLD. ApoE knockout (ApoE-/-) mice were exposed to CIH to induce NAFLD, and primary hepatocytes were also exposed to CIH to mimic in vitro setting. Accordingly, we found that RAGE and NF-κB were upregulated in the liver tissues of CIH-induced NAFLD mice and CIH-exposed hepatocytes. Depleted RAGE attenuated CIH-induced hepatocyte injury, lipid deposition, and inflammation. The relationship between RAGE and NF-κB was analyzed by in silico analysis and correlation analysis. It was demonstrated that knockdown of RAGE inhibited the NF-кB pathway, thus alleviating CIH-induced disorders in hepatocytes. Moreover, in vivo experiments also verified that depletion of RAGE alleviated CIH-induced NAFLD by inhibiting NF-кB pathway. Collectively, loss of RAGE blocked the NF-кB pathway to alleviate CIH-induced NAFLD, therefore, highlighting a potential hepatoprotective target for treating NAFLD.

Inhibition of the PD-1/PD-L1 signaling pathway enhances innate immune response of alveolar macrophages to mycobacterium tuberculosis in mice.

BACKGROUND: Mycobacterium tuberculosis (TB) is a pathogen that consequently leads to TB infection, which remains a significant global health concern. Programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling pathway is critical for terminating immune responses. The present study aimed to elucidate the regulatory role of the PD-1/PD-L1 signaling pathway in alveolar macrophages against Mycobacterium TB in mice. METHODS: Specific pathogen free mice were initially prepared for Mycobacterium TB model establishment. The alveolar macrophages of the successfully modeled rats were evaluated to determine the levels of PD-1, PD-L1, AKT, mTOR, TNF-α, NF-κB, IL-2, IL-4, IL-6, IL-10, IL-17, IL-17A, and IFN-γ. The surface makers of macrophages (CD11c, CD16, CD86, CD163, CD206, CX3CR-1 and CSF-1R), level of ROS, apoptosis and cell cycle, were all assessed. RESULTS: Elevated levels of PD-1 and PD-L1, decreased levels of AKT and mTOR, along with elevated levels of TNF-α, NF-κB, IL-17, IL-2, IL-6, IL-17A and IFN-γ were identified in the alveolar macrophages infected with Mycobacterium TB, while an opposite trend was observed when PD-1/PD-L1 signaling pathway was inhibited. Additionally, elevated protein levels of CD11c, CD16 and CD86, as well as an increased rate of positive ROS and cell apoptosis, levels of Bax, and a diminished percentage of alveolar macrophages at the S and G2/M stages were detected in the event of Mycobacterium TB infection. A contrasting trend to the aforementioned findings was detected when the PD-1/PD-L1 signaling pathway was inhibited. CONCLUSION: Taken together, these results suggested that inhibition of the PD-1/PD-L1 signaling pathway enhanced the innate immune response of alveolar macrophages to Mycobacterium TB in mice.

Activation of the High Mobility Group Box 1/Receptor for Advanced Glycation Endproducts /NOD-like Receptor Family Pyrin Domain-Containing 3 Axis Under Chronic Intermittent Hypoxia Induction Promotes the Progression of Atherosclerosis in ApoE-/- Mice.

Background Chronic intermittent hypoxia (CIH) has been regarded as an important cause of atherosclerotic disease. In our study, we set out to investigate whether CIH regulated the high mobility group box 1/receptor for advanced glycation endproducts/NOD-like receptor family pyrin domain-containing 3 (HMGB1/RAGE/NLRP3) axis to affect the progression of atherosclerosis. Methods and Results Initially, peripheral blood samples were collected from patients with single obstructive sleep apnea, atherosclerosis complicated with obstructive sleep apnea, and healthy volunteers. In vitro cell experiments were conducted using human monocyte cell line THP-1 and human umbilical vein endothelial cells to explore the role of HMGB1 in cell migration, apoptosis, adhesion, and transendothelial migration. In addition, a CIH-induced atherosclerosis mouse model was established for further identifying the critical role of the HMGB1/RAGE/NLRP3 axis in atherosclerosis. Upregulated HMGB1 and RAGE were found in patients with atherosclerosis complicated with obstructive sleep apnea. CIH induction increased HMGB1 expression by inhibiting HMGB1 methylation, activating the RAGE/NLRP3 axis. After inhibition of the HMGB1/RAGE/NLRP3 axis, monocyte chemotaxis and adhesion were repressed, and macrophage-derived foam cell formation was inhibited, accompanied by suppression of endothelial and foam cell apoptosis and inflammatory factor secretion. In vivo animal experiments also noted that the progression of atherosclerosis was prevented by inhibition of the HMGB1/RAGE/NLRP3 axis in CIH-induced ApoE-/- mice. Conclusions Taken together, CIH induction can upregulate HMGB1 through inhibition of HMGB1 methylation, which activates the RAGE/NLRP3 axis to promote inflammatory factor secretion, thereby promoting the progression of atherosclerosis.