LAUSR

ABSTRACT Acute respiratory distress syndrome (ARDS) is characterized by uncontrolled inflammation, which manifests as leukocyte infiltration and lung injury. However, the molecules that initiate this infiltration remain incompletely understood. We evaluated the effect of the nuclear alarmin interleukin (IL)-33 on lung damage and the immune response in lipopolysaccharide (LPS)-induced lung injury. We established a lipopolysaccharide (LPS)-induced lung injury mouse model. We used genetically engineered mice to investigate the relationship among the IL-33/ST2 axis, NKT cells, and ARDS. We found that IL-33 was localized to the nucleus in alveolar epithelial cells, from which it was released 1 hour after ARDS induction in wild-type (WT) mice. Mice lacking IL-33 (IL-33-/-) or ST2 (ST2-/-) exhibited reduced neutrophil infiltration, alveolar capillary leakage, and lung injury in ARDS compared to wild-type mice. This protection was associated with decreased lung recruitment and activation of invariant nature killer (iNKT) cells and activation of traditional T cells. Then, we validated that iNKT cells were deleterious in ARDS in CD1d-/- and Vα14Τg mice. Compared to wild-type mice, Vα14Τg mice exhibited increased lung injury in ARDS, and the CD1d-/- mice showed outcomes opposite those of the Vα14Τg mice. Furthermore, we administered a neutralizing anti-ST2 antibody to LPS-treated WT and Vα14Τg mice 1 h before LPS administration. We found that IL-33 promoted inflammation through NKT cells in ARDS. In summary, our results demonstrated that the IL-33/ST2 axis promotes the early uncontrolled inflammatory response in ARDS by activating and recruiting iNKT cells. Therefore, IL-33 and NKT cells may be therapeutic target molecules and immune cells, respectively, in early ARDS cytokine storms.