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Functional Remodeling of iNKT Cells by Sulfatide-Reactive Type II NKT Cells Reprograms Alveolar Macrophages to Alleviate Lung Ischemia-Reperfusion Injury

ABSTRACT:

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 3A (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.

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13533 | MetaboLights | 2025-12-19

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13533_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13533_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13533.txt	Txt

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Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

Dataset Information

Functional Remodeling of iNKT Cells by Sulfatide-Reactive Type II NKT Cells Reprograms Alveolar Macrophages to Alleviate Lung Ischemia-Reperfusion Injury

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