MCTR1 ameliorates LPS-induced lung injury by inhibiting neutrophil reverse transendothelial migration

Dysregulated inflammatory responses during sepsis often result in acute lung injury (ALI). Neutrophils activated at the primary site of injury can re-enter the circulation through reverse transendothelial migration (rTEM), subsequently infiltrating other organs and contributing to systemic inflammation and multi-organ damage. The specialized pro-resolving lipid mediator (SPM) maresin conjugate in tissue regeneration 1 (MCTR1) has been shown to mitigate organ injury in sepsis. This study investigated the role of neutrophil rTEM in ALI and examined whether MCTR1 can alleviate ALI by modulating neutrophil rTEM.

Lung injury was induced in mice by administrating lipopolysaccharide (LPS). Lung damage was assessed using H&E staining, lung wet-to-dry ratio, inflammatory mediator levels, and protein content in the bronchoalveolar lavage fluid. Neutrophil infiltration in lung tissue was evaluated by immunofluorescence, and flow cytometry was used to quantify rTEM neutrophils. Protein expression of neutrophil elastase (NE) and junctional adhesion molecule-C (JAM-C) was analyzed to assess rTEM activity. The role of CXCR4 in neutrophil rTEM was investigated using the CXCR4 inhibitor AMD3100. Additionally, bone marrow-derived neutrophils were isolated to evaluate the effects of MCTR1 on CXCR4 and GRK2 expression.

MCTR1 alleviated lung injury and inhibited neutrophils rTEM in LPS-induced lung injury. MCTR1 also decreased NE expression and increased JAM-C expression. The CXCR4 inhibitor AMD3100 effectively suppressed neutrophil rTEM and alleviated lung injury. Furthermore, MCTR1 inhibited CXCR4 expression and enhanced GRK2 expression.

MCTR1 reduces lung damage by upregulating GRK2 to inhibit CXCR4 expression, thereby suppressing neutrophil rTEM in LPS-induced lung injury.