Receptor for Advanced Glycation End Products (RAGE) on iNKT Cells Mediates Lung Ischemia–Reperfusion Injury

• Published in: American journal of transplantation Vol. 13; no. 9; pp. 2255 - 2267
• Main Authors: Sharma, A. K., LaPar, D. J., Stone, M. L., Zhao, Y., Kron, I. L., Laubach, V. E.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01-09-2013; Elsevier Limited
• Subjects: Alveolar macrophages; Animals; Biological and medical sciences; Cell Line; HMGB1; HMGB1 Protein - biosynthesis; HMGB1 Protein - pharmacology; IL‐17; Immune system; iNKT cells; Interleukin-17 - biosynthesis; Ischemia; Lung - immunology; Lung - physiopathology; lung transplantation; Macrophages, Alveolar - physiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Natural Killer T-Cells - immunology; Neutrophil Infiltration - physiology; RAGE; Receptor for Advanced Glycation End Products; Receptors, Immunologic - physiology; Reperfusion Injury - physiopathology; Rodents; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Temperature; Lung; Environmental factor; Cardiovascular disease; Transplantation; HMGB1; Homotransplantation; Respiratory system; Advanced glycation end products; Reperfusion; Ischemia; Receptor for advanced glycation endproducts; Surgery; Graft; Cell; Biological receptor; Lung disease; Cold; Respiratory disease; iNKT cells; RAGE; Alveolar macrophages; Interleukin 17; Treatment; IL-17; lung transplantation; Macrophage
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12368

Activation of invariant natural killer T (iNKT) cells and signaling through receptor for advanced glycation end products (RAGE) are known to independently mediate lung ischemia–reperfusion (IR) injury. This study tests the hypothesis that activation of RAGE specifically on iNKT cells via alveolar macrophage‐produced high mobility group box 1 (HMGB1) is critical for the initiation of lung IR injury. A murine in vivo hilar clamp model was utilized, which demonstrated that RAGE−/− mice were significantly protected from IR injury. Treatment of WT mice with soluble RAGE (a decoy receptor), or anti‐HMGB1 antibody, attenuated lung IR injury and inflammation, whereas treatment with recombinant HMGB1 enhanced IR injury in WT mice but not RAGE−/− mice. Importantly, lung dysfunction, cytokine production and neutrophil infiltration were significantly attenuated after IR in Jα18−/− mice reconstituted with RAGE−/− iNKT cells (versus WT iNKT cells). In vitro studies demonstrated that, after hypoxia‐reoxygenation, alveolar macrophage‐derived HMGB1 augmented IL‐17 production from iNKT cells in a RAGE‐dependent manner. These results suggest that HMGB1‐mediated RAGE activation on iNKT cells is critical for initiation of lung IR 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 IR injury.
This study uses a murine in vivo lung ischemia reperfusion model and in vitro experiments to demonstrate that macrophage‐produced HMGB1 mediates RAGE activation on iNKT cells to induce IL‐17 production, which is critical for neutrophil infiltration and initiation of lung ischemia reperfusion injury. See editorial by Gelman and Scozzi on page 2237.