Importance of Toll-like receptor 2 in mitochondrial dysfunction during polymicrobial sepsis
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Published on: July 26, 2017
1From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (Y.G., L.Z., Y.F., D.L., J.C., W.C.); and Key Laboratory for Major Obstetric Diseases, Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (Y.G., D.C.).
Background:
Toll-like receptor 2 (TLR2) contributes to sepsis pathogenesis such as deleterious systemic inflammation, cardiac dysfunction, and high mortality in animal studies. Mitochondrial dysfunction is a key molecular event that is associated with organ injury in sepsis. The role of TLR2 in sepsis-induced mitochondrial dysfunction remains unclear.
Methods:
Intracellular hydrogen peroxide (H2O2), mitochondrial superoxide (O2), mitochondrial membrane potential (ΔΨm), and intracellular adenosine triphosphate (ATP) were measured in peritoneal leukocytes. A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). Wild-type and TLR2-deficient (TLR2) mice were subjected to sham or CLP. Mitochondrial functions including reactive oxygen species (ROS), ΔΨm, intracellular ATP, and complex III activity were measured.
Results:
TLR2/1 activation by Pam3Cys enhanced intracellular H2O2 and mitochondrial O2 production in leukocytes, but had no effect on mitochondrial ΔΨm and ATP production. The effect was specific for TLR2/1 as TLR3 or TLR9 ligands did not induce ROS production. Polymicrobial sepsis induced mitochondrial dysfunction in leukocytes, as demonstrated by increased H2O2 and mitochondrial O2- production (CLP vs. sham; H2O2: 3,173±498, n=5 vs. 557±38, n=4; O2-: 707±66, n=35 vs. 485±35, n=17, mean fluorescence intensity, mean±SEM), attenuated complex III activity (13±2, n=16 vs. 30±3, n=7, millioptical densities/min), loss of mitochondrial ΔΨm, and depletion of intracellular ATP (33±6, n=11 vs. 296±29, n=4, nmol/mg protein). In comparison, there was significant improvement in mitochondrial function in septic TLR2-/- mice as evidenced by attenuated mitochondrial ROS production, better-maintained mitochondrial ΔΨm, and higher cellular ATP production.
Conclusions:
TLR2 signaling plays a critical role in mediating mitochondrial dysfunction in peritoneal leukocytes during polymicrobial sepsis.
Insights
Toll-like receptor 2 (TLR2) exacerbates mitochondrial dysfunction and inflammation during sepsis. Blocking TLR2 in mice improved mitochondrial function and reduced sepsis-induced damage, highlighting TLR2's critical role.
Area of Science:
- Immunology
- Mitochondrial Biology
- Sepsis Pathogenesis
Background:
- Toll-like receptor 2 (TLR2) is implicated in sepsis pathogenesis, contributing to inflammation, cardiac dysfunction, and mortality.
- Mitochondrial dysfunction is a key factor in sepsis-related organ injury.
- The specific role of TLR2 in sepsis-induced mitochondrial dysfunction is not well understood.
Purpose of the Study:
- To investigate the role of Toll-like receptor 2 (TLR2) in sepsis-induced mitochondrial dysfunction in peritoneal leukocytes.
- To determine if TLR2 activation influences mitochondrial function during sepsis.
Main Methods:
- Mice (wild-type and TLR2-deficient) were subjected to polymicrobial sepsis via cecum ligation and puncture (CLP) or sham surgery.
- Mitochondrial functions, including reactive oxygen species (ROS) production (H2O2, O2-), mitochondrial membrane potential (ΔΨm), intracellular ATP levels, and complex III activity, were measured in peritoneal leukocytes.
- TLR2/1 activation was induced using Pam3Cys to assess its specific effects on mitochondrial parameters.
Main Results:
- Polymicrobial sepsis induced significant mitochondrial dysfunction in wild-type mice, characterized by increased ROS, reduced mitochondrial membrane potential, and depleted ATP.
- TLR2-deficient mice exhibited improved mitochondrial function during sepsis, with attenuated ROS production and better-maintained mitochondrial membrane potential and ATP levels.
- TLR2/1 activation by Pam3Cys increased ROS production in leukocytes but did not affect mitochondrial membrane potential or ATP levels.
Conclusions:
- Toll-like receptor 2 (TLR2) signaling is critical in mediating mitochondrial dysfunction in peritoneal leukocytes during polymicrobial sepsis.
- Targeting TLR2 may represent a therapeutic strategy to mitigate sepsis-induced mitochondrial injury and improve outcomes.
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