Role of RAGE Signaling in Lung IR Injury
PI: Victor Laubach, PhD
The receptor for advanced glycation end products (RAGE) is a ubiquitous, multiligand receptor implicated in a variety of pathological conditions such as diabetes and its complications, cancer, cardiovascular disease and inflammation. Activation of RAGE occurs through the binding of a number of identified ligands, including amyloid-B peptide, amyloid A, a group of non-enzymatically glycated byproducts known as advanced glycated endproducts (AGEs), the S100/calgranulin family of calcium-binding polypeptides, and the DNA binding protein HMGB1 (high mobility group box 1). Once activated, RAGE mediates its downstream effects through several different signaling pathways, including generation of reactive oxygen species via NADPH oxidase, activation of NF-kB, and activation of ERK1/2 MAP kinase, SAPK/JNK MAP kinase, or JAK/STAT signaling pathways. RAGE is highly expressed in the lung where it resides on the basolateral membrane of alveolar epithelial type I cells as well as other cell types including smooth muscle cells, endothelial cells and mononuclear phagocytes.
We are studying the role of RAGE signaling in lung IR injury with a focus on the HMGB1 ligand and RAGE signaling in iNKT cells and macrophages. Results to date suggest that HMGB1-mediated RAGE activation on iNKT cells is critical for initiation of lung ischemia-reperfusion injury and that a crosstalk between macrophages and iNKT cells via the HMGB1/RAGE axis mediates IL-17 production by iNKT cells causing neutrophil infiltration and lung ischemia-reperfusion injury.