Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury

A. K. Sharma, D. J. Lapar, M. L. Stone, Y. Zhao, I. L. Kron, V. E. Laubach

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2255-2267
Number of pages13
JournalAmerican Journal of Transplantation
Issue number9
StatePublished - Sep 2013


  • Alveolar macrophages
  • HMGB1
  • IL-17
  • RAGE
  • iNKT cells
  • lung transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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