Upregulation of Matrix Metalloproteinase‐9 Protects against Sepsis‐Induced Acute Lung Injury via Promoting the Release of Soluble Receptor for Advanced Glycation End Products

Abstract

Dysregulation of matrix metalloproteinase- (MMP-) 9 is implicated in the pathogenesis of acute lung injury (ALI). However, it remains controversial whether MMP-9 improves or deteriorates acute lung injury of different etiologies. The receptor for advanced glycation end products (RAGE) plays a critical role in the pathogenesis of acute lung injury. MMPs are known to mediate RAGE shedding and release of soluble RAGE (sRAGE), which can act as a decoy receptor by competitively inhibiting the binding of RAGE ligands to RAGE. Therefore, this study is aimed at clarifying whether and how pulmonary knockdown of MMP-9 affected sepsis-induced acute lung injury as well as the release of sRAGE in a murine cecal ligation and puncture (CLP) model. The analysis of GEO mouse sepsis datasets GSE15379, GSE52474, and GSE60088 revealed that the mRNA expression of MMP-9 was significantly upregulated in septic mouse lung tissues. Elevation of pulmonary MMP-9 mRNA and protein expressions was confirmed in CLP-induced mouse sepsis model. Intratracheal injection of MMP-9 siRNA resulted in an approximately 60% decrease in pulmonary MMP-9 expression. It was found that pulmonary knockdown of MMP-9 significantly increased mortality of sepsis and exacerbated sepsis-associated acute lung injury. Pulmonary MMP-9 knockdown also decreased sRAGE release and enhanced sepsis-induced activation of the RAGE/nuclear factor-κB (NF-κB) signaling pathway, meanwhile aggravating sepsis-induced oxidative stress and inflammation in lung tissues. In addition, administration of recombinant sRAGE protein suppressed the activation of the RAGE/NF-κB signaling pathway and ameliorated pulmonary oxidative stress, inflammation, and lung injury in CLP-induced septic mice. In conclusion, our data indicate that MMP-9-mediated RAGE shedding limits the severity of sepsis-associated pulmonary edema, inflammation, oxidative stress, and lung injury by suppressing the RAGE/NF-κB signaling pathway via the decoy receptor activities of sRAGE. MMP-9-mediated sRAGE production may serve as a self-limiting mechanism to control and resolve excessive inflammation and oxidative stress in the lung during sepsis.

Identification and Validation of Pathogenic Genes in Sepsis and Associated Diseases by Integrated Bioinformatics Approach

“…Etiologies such as sepsis were implicated in the activation of the RAGE-dependent NF-kB signaling cascade associated with inflammatory processes and oxidative stress [ 75 ]. Zhang H et al reported that MMP9 mediated the shedding of RAGE , and might exacerbate sepsis-associated pulmonary inflammation by controlling RAGE/NF-κB signaling [ 76 ]. MMP9 is also considered to be a macrophage gene [ 77 ], where its overexpression in the lung tissue of septic mice model correlates with our study.…”

Soluble Receptor for Advanced Glycation End Product Is Involved in the Inflammatory Response of Human Adenovirus-Infected Patients

“…MMP9 is one of the key enzymes involved in the production of sRAGE. MMP9-mediated sRAGE production inhibited the RAGE/NF-κB activation and consequently reduced the severity of pulmonary edema, inflammation, and oxidative stress ( Zhang et al, 2021 ). During SARS-CoV-2 infection, patients showed increased expression of MMP9 compared to controls ( Gelzo et al, 2022 ).…”

“…Moreover, the extracellular domain of RAGE is cleaved by the metalloproteinases ADAM10 and metalloprotease 9 (MMP9), and the extracellular segment of RAGE is released, forming soluble RAGE (sRAGE) ( Metz et al, 2012 ). sRAGE acts as a decoy and binds to RAGE ligands, reducing RAGE activation ( Zhang et al, 2021 ). These processes form an elegant negative-feedback loop to contain RAGE concentrations and activation, and control the extent of inflammatory responses.…”

Antioxidants as Therapeutic Agents in Acute Respiratory Distress Syndrome (ARDS) Treatment—From Mice to Men

“…Mechanistically, ROS contribute to the damage of the epithelial barrier. ROS-dependent induction of the matrix metalloproteinase (MMP)-9 causes damage, internalization, and downregulation of proteins of intercellular connections, so-called tight junctions [ 150 ], such as claudins, occludins, and E-cadherins, linking the extracellular glycocalyx with the intracellular cytoskeleton ( Figure 4 a) [ 151 , 152 ]. The loss of cell–cell interactions consequently is associated with an increase in permeability and gap formation [ 117 ], leading to edema formation [ 153 ].…”