Functional remodeling of iNKT cells by sulfatide-reactive type II NKT cells reprograms alveolar macrophages to alleviate lung ischemia-reperfusion injury

Lung ischemia-reperfusion injury (LIRI) is a serious complication in critical clinical situations. Despite its importance, the specific role of type II natural killer T (NKT) cells in LIRI remains unclear. In this study, we establish a LIRI mouse model and demonstrate that sulfatide-reactive type II NKT cells promote M2 polarization of alveolar macrophages (AMs) and alleviate LIRI through AMs-mediated mechanisms. This protective effect is absent in Jα18−/- mice, indicating the essential role of invariant NKT (iNKT) cells. Further analysis shows that interleukin-10 (IL-10) secreted by iNKT cells upregulates AT-rich interaction domain 3 A (Arid3a) in macrophages, which then promotes the transcription of DNA damage inducible transcript 4 (DDIT4). This cascade enhances M2 polarization of macrophages, potentially contributing to lung protection and alleviating LIRI. These findings suggest that NKT cells may offer a therapeutic target for LIRI in the future. Mechanistic modeling of sulfatide-reactive type II NKT cells reveals their role in regulating M2 polarization of alveolar macrophages through the iNKT cell–IL-10 axis, thereby alleviating lung ischemia–reperfusion injury.