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Published on: August 12, 2019
Macrophage S1PR2 Drives Sepsis-induced Immunosuppression by Exacerbating Mitochondrial Fragmentation
Xiangyang Yu1, Xin Hu1, Dongdong Wang1
1Department of Anesthesiology, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China.
Abstract:
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 (n = 12), nonseptic critical control subjects (n = 13), and patients with sepsis (n = 19). Peritoneal macrophages were harvested from wild-type and S1pr2-/- 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.
Insights
Sphingosine-1-phosphate receptor 2 (S1PR2) drives sepsis-induced immunosuppression by causing macrophage mitochondrial fragmentation. Inhibiting S1PR2 protects against sepsis, suggesting it as a therapeutic target.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Macrophage mitochondrial dysfunction contributes to sepsis-induced immunosuppression and poor patient outcomes.
- Mitochondrial fragmentation is a key driver of mitochondrial dysfunction.
- Sphingosine-1-phosphate receptor 2 (S1PR2) influences macrophage function in sepsis, but its role in immunosuppression requires elucidation.
Purpose of the Study:
- To investigate the link between macrophage mitochondrial fragmentation and sepsis-induced immunosuppression.
- To explore the underlying mechanisms involving S1PR2.
Main Methods:
- Analysis of peripheral blood monocytes from healthy controls, nonseptic critical patients, and sepsis patients.
- Harvesting peritoneal macrophages from wild-type and S1pr2 knockout mice post-cecal ligation and puncture (CLP).
- Evaluation of mitochondrial ultrastructure via transmission electron microscopy and assessment of immunosuppression markers like HLA-DR.
Main Results:
- Sepsis patients displayed elevated S1PR2, mitochondrial fragmentation, and dysfunction in monocytes compared to controls.
- Mitochondrial fragmentation correlated negatively with HLA-DR expression, while S1PR2 expression correlated positively with fragmentation and negatively with HLA-DR.
- S1PR2 deficiency in mice reduced mitochondrial fragmentation and dysfunction, enhanced immunity, and improved survival after CLP.
- S1PR2 activation of ROCK I leads to Drp1 phosphorylation, causing mitochondrial fragmentation and immunosuppression, which was reversed by Drp1 inhibition (Mdivi-1).
Conclusions:
- S1PR2-mediated mitochondrial fragmentation is a critical mechanism underlying septic immunosuppression.
- Targeting S1PR2 presents a potential therapeutic strategy for improving sepsis prognosis.
