Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance.
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).


CONCLUSIONS
The study data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis possibly by regulating HO-1 expression.
From 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.).
XiaoWei
X
Qian
Tomohiro
T
Numata
Kai
K
Zhang
CaiXia
C
Li
JinChao
J
Hou
Yasuo
Y
Mori
XiangMing
X
Fang
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001419:Bacteria; D015153:Blotting, Western; D001822:Body Burden; D001854:Bone Marrow Cells / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology; D009929:Organ Size / Q000502:physiology; D018408:Patch-Clamp Techniques; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics* / Q000382:microbiology* / Q000401:mortality; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase; D002118:Calcium