Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis

Plitas G., et al. 2008. J. Exp. Med. 205:1277-1283.

Speaker : Chia-Ming Liu (劉佳明)                         Time: 13:10~14:00, Dec.24, 2008

Commentator: Dr. Chiou-Feng Lin (林秋烽博士)  Place: Room 601

Abstract:

Sepsis affects approximately 700,000 people annually and accounts for about 210,000 deaths per year in the US¹. In Taiwan, sepsis is the tenth causes of deaths in 2007.² Sepsis is defined as a complex interaction between the microorganism and the host immune system. The innate immune cells recognize conserved microbial components via pattern-recognition receptors such as Toll-like receptors (TLRs).There are at least 10 TLRs in mammals and different microbial products bind to different Toll-like receptors, such as TLR-4 recognizes a lipopolysaccharide of gram-negative bacteria, and TLR-2 recognizes a peptidoglycan of gram-positive bacteria. The genetic deficiency of MyD88, but not of TLR2 and TLR4, protected mice against septic peritonitis, suggesting that stimulation of multiple TLRs is needed for an overwhelming inflammatory response³. In this paper, the role of TLR9 in the dysregulated immune response and death associated polymicrobial sepsis was studied. After experimental peritonitis induced by cecal ligation and puncture (CLP), TLR9^-/- mice are resistant to polymicrobial sepsis, presenting lower serum inflammatory cytokines levels, greater survival, and higher bacteria clearance compared with wild type mice. Protection of TLR9^-/- mice was associated with a greater amount of peritoneal dendritic cells (DCs) and granulocytes post induction. Adoptive transfer of TLR9^-/- DCs to WT mice provides a greater accumulation of transferred TLR9^–/– DCs and peritoneal granulocytes in the peritoneum of WT mice after CLP. The iCpG sequence as a TLR9 blockade was administered into WT mice and found to provide the protection to polymicrobial sepsis. This finding suggests that injurious immune response to bacterial sepsis occurs via TLR9 stimulation and TLR9 blockade can be considered as a treatment of sepsis.

References:

1.          Riedemann, N.C. , et al. 2003. The enigma of sepsis. J. Clin. Invest. 112:460–467.

2.       中華民國九十六年台北市生命統計；台北市政府衛生局；中華民國九十七年八月編印。

3.          Weighardt, H. , et al. 2002. Cutting edge: myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection. J. Immunol. 169:2823–2827.