Importance of Toll-like receptor 2 in mitochondrial dysfunction during polymicrobial sepsis.

Abstract

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.

• Authors: Yu Gong, Lin Zou, Yan Feng, Dan Li, Jiayan Cai, Dunjin Chen, Wei Chao
• Journal: Anesthesiology (Anesthesiology) Vol. 121 Issue 6 Pg. 1236-47 (Dec 2014) ISSN: 1528-1175 [Electronic] United States
• PMID: 25272245 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• High Mobility Group Proteins
• Reactive Oxygen Species
• Tfam protein, mouse
• Toll-Like Receptor 2
• Cyclooxygenase 2

Topics

• Animals
• Ascitic Fluid (pathology)
• Cyclooxygenase 2 (genetics)
• DNA-Binding Proteins (genetics)
• Gene Expression (genetics)
• High Mobility Group Proteins (genetics)
• Leukocytes
• Membrane Potential, Mitochondrial (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Diseases (etiology, physiopathology)
• Reactive Oxygen Species (metabolism)
• Sepsis (complications, physiopathology)
• Toll-Like Receptor 2 (genetics)