title: Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury.
abstract: 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.
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA.
authors.forename: A K
authors.initials: AK
authors.lastname: Sharma
authors.forename: D J
authors.initials: DJ
authors.lastname: LaPar
authors.forename: M L
authors.initials: ML
authors.lastname: Stone
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: I L
authors.initials: IL
authors.lastname: Kron
authors.forename: V E
authors.initials: VE
authors.lastname: Laubach
mesh_terms: D000818:Animals; D002460:Cell Line; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000494:pharmacology; D020381:Interleukin-17 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D016676:Macrophages, Alveolar / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology; D020556:Neutrophil Infiltration / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology*
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D020381:Interleukin-17; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: Alveolar macrophages; HMGB1; IL-17; RAGE; iNKT cells; lung transplantation