Macrophage S1PR2 Drives Sepsis-induced Immunosuppression by Exacerbating Mitochondrial Fragmentation

Macrophage mitochondrial dysfunction is associated with immunosuppression and poor prognosis of patients with sepsis. Mitochondrial fragmentation drives mitochondrial dysfunction. Our previous study has found that S1PR2 (sphingosine-1-phosphate receptor 2) regulates macrophage phagocytosis during sepsis, whereas the role of S1PR2 in immunosuppression and the mechanisms require further study. This study aimed to unveil the relationship between macrophage mitochondrial fragmentation and sepsis-induced immunosuppression, as well as the S1PR2-related mechanisms thereof. Peripheral blood monocytes were collected from healthy control subjects (<i>n</i> = 12), nonseptic critical control subjects (<i>n</i> = 13), and patients with sepsis (<i>n</i> = 19). Peritoneal macrophages were harvested from wild-type and <i>S1pr2</i>^-/- mice (Mutant Mouse Regional Resource Centers strain ID, 12830) after cecal ligation and puncture (CLP). Mitochondrial ultrastructure was evaluated using transmission electron microscopy. The impact of mitochondrial ultrastructure alteration on immunosuppression of monocyte-macrophages was evaluated. Compared with nonseptic and healthy control subjects, peripheral blood monocytes from patients with sepsis exhibited increased S1PR2 expression, mitochondrial fragmentation, and mitochondrial dysfunction. Mitochondrial fragmentation was negatively associated with HLA-DR (human leukocyte antigen-DR isotype) expression. S1PR2 expression was positively correlated with mitochondrial fragmentation and negatively correlated with HLA-DR expression. In mice subjected to CLP, S1PR2 depletion ameliorated macrophage mitochondrial fragmentation and dysfunction, boosted immunity, and improved survival. Mechanistically, in response to sepsis, S1PR2 activates ROCK I to induce Drp1 phosphorylation, resulting in Drp1-dependent mitochondrial fragmentation of macrophages. Drp1 inhibition by Mdivi-1 mitigated S1PR2-induced macrophage immunosuppression and improved the prognosis of mice after CLP. In conclusion, S1PR2-induced mitochondrial fragmentation is a crucial factor mediating septic immunosuppression, highlighting its potential as a promising therapeutic target in sepsis.