title: Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury.
abstract: BACKGROUND
  We recently implicated a role for CD4(+) T cells and demonstrated elevated IL-17A expression in lung ischemia-reperfusion (IR) injury. However, identification of the specific subset of CD4(+) T cells and their mechanistic role in IR injury remains unknown.
  
  
  OBJECTIVE
  We tested the hypothesis that invariant natural killer T (iNKT) cells mediate lung IR injury via IL-17A signaling.
  
  
  METHODS
  Mice underwent lung IR via left hilar ligation. Pulmonary function was measured using an isolated lung system. Lung injury was assessed by measuring edema (wet/dry weight) and vascular permeability (Evans blue dye). Inflammation was assessed by measuring proinflammatory cytokines in lungs, and neutrophil infiltration was measured by immunohistochemistry and myeloperoxidase levels.
  
  
  RESULTS
  Pulmonary dysfunction (increased airway resistance and pulmonary artery pressure and decreased pulmonary compliance), injury (edema, vascular permeability), and inflammation (elevated IL-17A; IL-6; tumor necrosis factor-α; monocyte chemotactic protein-1; keratinocyte-derived chemokine; regulated upon activation, normal T-cell expressed and secreted; and neutrophil infiltration) after IR were attenuated in IL-17A(-/-) and Rag-1(-/-) mice. Anti-IL-17A antibody attenuated lung dysfunction in wild-type mice after IR. Reconstitution of Rag-1(-/-) mice with wild-type, but not IL-17A(-/-), CD4(+) T cells restored lung dysfunction, injury, and inflammation after IR. Lung dysfunction, injury, IL-17A expression, and neutrophil infiltration were attenuated in Jα18(-/-) mice after IR, all of which were restored by reconstitution with wild-type, but not IL-17A(-/-), iNKT cells. Flow cytometry and enzyme-linked immunosorbent spot assay confirmed IL-17A production by iNKT cells after IR.
  
  
  CONCLUSIONS
  These results demonstrate that CD4(+) iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism.
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Damien J
authors.initials: DJ
authors.lastname: LaPar
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D011654:Pulmonary Edema / Q000276:immunology / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism; D012129:Respiratory Function Tests
chemical_list: D020381:Interleukin-17