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Injections of Lipopolysaccharide into Mice to Mimic Entrance of Microbial-derived Products After Intestinal Barrier Breach
Published on: May 2, 2018
Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance
XiaoWei Qian1, Tomohiro Numata, Kai Zhang
1From the Department of Anaesthesia, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China (X.Q., K.Z., C.L., J.H., X.F.); and Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan (T.N., Y.M.).
Background:
Recent studies suggest that the transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remain unclear.
Methods:
The authors explored the effects of genetic disruption of TRPM2 on mortality (n = 15), bacterial clearance (n = 6), organ injury, and systemic inflammation during cecal ligation and puncture-induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis.
Results:
After cecal ligation and puncture, Trpm2-knockout mice had increased mortality compared with wild-type mice (73.3 vs. 40%, P = 0.0289). The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. TRPM2-mediated Ca influx plays an important role in lipopolysaccharide or cecal ligation and puncture-induced heme oxygenase-1 (HO-1) expression in macrophage. HO-1 up-regulation decreased bacterial burden both in wild-type bone marrow-derived macrophages and in cecal ligation and puncture-induced septic wild-type mice. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow-derived macrophages. Pretreatment of Trpm2-knockout bone marrow-derived macrophages with HO-1 inducer markedly increased HO-1 expression and decreased bacterial burden. Pretreatment of Trpm2-knockout mice with HO-1 inducer reversed the susceptibility of Trpm2-knockout mice to sepsis by enhancing the bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 messenger RNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 messenger RNA levels. TRPM2 levels correlated with HO-1 levels in septic patients (r = 0.675, P = 0.001).
Conclusion:
The study data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis possibly by regulating HO-1 expression.
Insights
The transient receptor potential melastatin 2 (TRPM2) channel protects against sepsis by enhancing bacterial clearance, potentially through regulating heme oxygenase-1 (HO-1) expression. TRPM2 deficiency increases sepsis mortality and bacterial burden.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- The transient receptor potential melastatin 2 (TRPM2) channel is implicated in inflammation and immune responses.
- The specific role and mechanism of TRPM2 in polymicrobial sepsis are not well understood.
Purpose of the Study:
- To investigate the role of TRPM2 in polymicrobial sepsis using a mouse model.
- To elucidate the underlying mechanisms of TRPM2's function in sepsis, including its relationship with heme oxygenase-1 (HO-1).
Main Methods:
- Cecal ligation and puncture (CLP) model in Trpm2-knockout and wild-type mice.
- Assessment of mortality, bacterial clearance, organ injury, and systemic inflammation.
- Analysis of TRPM2-mediated calcium influx and HO-1 expression in macrophages and patient samples using electrophysiology, immunoblotting, qPCR, and correlation studies.
Main Results:
- Trpm2-knockout mice exhibited significantly increased mortality, bacterial burden, organ injury, and systemic inflammation compared to wild-type mice after CLP.
- TRPM2 mediates calcium influx crucial for lipopolysaccharide (LPS)-induced HO-1 expression in macrophages. HO-1 upregulation reduced bacterial burden.
- Septic patients with lower TRPM2 and HO-1 mRNA levels showed worse outcomes, with TRPM2 levels correlating positively with HO-1 levels.
Conclusions:
- TRPM2 plays a protective role in polymicrobial sepsis by enhancing bacterial clearance.
- TRPM2 regulates HO-1 expression, which is critical for controlling bacterial burden during sepsis.
- TRPM2 and HO-1 represent potential therapeutic targets for sepsis management.
