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Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury.
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ABSTRACT: Rationale
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.Objectives
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.Measurements and main 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-?; 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 J?18(-/-) 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.
SUBMITTER: Sharma AK
PROVIDER: S-EPMC3137143 | biostudies-literature | 2011 Jun
REPOSITORIES: biostudies-literature
Publications
Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury.
American journal of respiratory and critical care medicine 20110211 11
<h4>Rationale</h4>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.<h4>Objectives</h4>We tested the hypothesis that invariant natural killer T (iNKT) cells mediate lung IR injury via IL-17A signaling.<h4>Methods</h4>Mice underwent lung IR via left hilar ligation. Pulmonary function was measur ...[more]