Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury

Abstract

Rationale: We recently implicated a role for CD4 1 T cells and demonstrated elevated IL-17A expression in lung ischemia-reperfusion (IR) injury. However, identification of the specific subset of CD4 1 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-a; 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 2/2 and Rag-1 2/2 mice. Anti-IL-17A antibody attenuated lung dysfunction in wildtype mice after IR. Reconstitution of Rag-1 2/2 mice with wild-type, but not IL-17A 2/2 , CD4 1 T cells restored lung dysfunction, injury, and inflammation after IR. Lung dysfunction, injury, IL-17A expression, and neutrophil infiltration were attenuated in Ja18 2/2 mice after IR, all of which were restored by reconstitution with wild-type, but not IL-17A 2/2 , 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 1 iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism.

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

“…Previous reports suggested that CD4 + T cells, NKT cells, and gd T cells produce IL-17A (26,36,37). Specifically, CD8 + cells produce IL-17A in patients with chronic obstructive pulmonary disease (38).…”

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

“…NKT cells initiate inflammation following IRI in liver, lung, and/or kidney (4,5). By studying NKT cell-deficient mice and by blocking DC-NKT cell interaction, we demonstrated that CD1d-restricted NKT cells are necessary for kidney IRI.…”

“…We and others have shown that NKT cells contribute to organ IRI (5,6,48,49). Interrupting the DC-NKT cell interaction, depleting CD1d-restricted NKT cells, or using NKT cell-deficient mice (CD1d KO) protected kidney from IRI (6).…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…neutrophil/mononuclear phagocyte activation and infiltration) (30), and proinflammatory cytokines and chemokines (7,8,15,20,24), all exemplifying multiple complex inflammatory pathways involved in PGD.…”