Role of UPP1 triggering TIM4-mediated efferocytosis and M2 polarization in alveolar macrophages to promote the resolution of inflammation in acute lung injury/acute respiratory distress syndrome

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is associated with high mortality. Impaired efferocytosisof alveolar macrophages (AMs) is a key factor contributing to poor clinical outcomes, yet the molecular mechanisms regulating this process remain unclear. The efferocytosis in LPS-induced AMs and ALI/ARDS mice model were evaluated by flow cytometry and immunofluorescence staining. The expression levels of uridine phosphorylase 1 (UPP1), T-cell immunoglobulin and mucin domain containing 4 (TIM4) in AMs were both detected in in vivo and in vitro . In vitro , UPP1 knockdown/overexpression experiments were performed to evaluate changes of efferocytosis and macrophage polarization in LPS stimulated AMs. In vivo , UPP1 overexpression and TIM4 neutralizing antibody intervention were performed to observe the changes of efferocytosis, macrophage polarization, inflammation factors and the repair of lung injury. Efferocytosis was downregulated in LPS-induced ALI/ARDS animal models, whereas LPS stimulation led to the upregulation of efferocytosis in in vitro AMs. In-depth mechanistic investigations revealed that the LPS-induced enhancement of efferocytosis was positively correlated with the increased expression of UPP1. And UPP1 promoted the phosphorylation of STAT3, thereby upregulating TIM4 signaling to mediate the augmentation of efferocytosis. Further, UPP1 upregulation abrogated the inhibitory effect on efferocytosis in ALI/ARDS and mitigated lung injury. UPP1 regulates AMs efferocytosis and M2 polarization via the STAT3-TIM4 axis, promoting inflammatory resolution in ALI/ARDS. This study provides a novel therapeutic target for ALI/ARDS treatment.