TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events

Karen A., et al. Journal of Experimental Medicine 205, 2609-2621 (2008).

Student: Jui-In Kai (蓋如茵)                                   Time: 13:00~14:00, Feb. 18, 2009

Commentator: Dr. Shun-Hua Chen (陳舜華)        Place: Room 601

Abstract

        Toll-like receptors (TLRs) of innate immune cells can recognize conserved microbial components through pathogen-associated molecular patterns (PAMPs), which activate inflammatiory responses by producing cytokines and chemokines. However, excessive inflammation is pathogenic for health and is involved in pathogenesis of sepsis [1]. Double-stranded RNA is recognized by TLR3, which induces macrophage activation followed by releasing inflammatory mediators to damage cells or tissues [2]. However, the pathogenesis of TLR3 responsed to RNA from dying cells during acute inflammatory processes remains unclear. In this study [3], the authors investigated the role of TLR3 using the models of experimental polymicrobial septic peritonitis and ischemic gut injury condition without exogenous viral stimulus. Compared with wild type, neutrophil recruitment and inflammatory cytokine production were higher in TLR3 knockout mice. However, TLR3 knockout mice were protected from the lethal effect caused by CLP surgery and present less tissue damage after gut ischemia. In these mice, proinflammatory cytokines quickly returned to baseline at late phase after CLP surgery and gut ischemia. In vitro studies demonstrated the peritoneal macrophages from TLR3 knockout mice were less response to RNA from necrotic PMN. Blocking TLR3 with antibody reduced necrotic cells-induced inflammatory responses. After CLP surgery or gut ischemia, post-treatment of TLR3 antibody significantly attenuated tissue damage and sepsis-induced mortality in vivo. Taken together, these data demonstrate that TLR3 is acted as an endogenous sensor of RNA from necrotic cells and is a regulator of the amplification of inflammatory responses.

 References

1.      Jonathan C., et al. The immunopathogenesis of sepsis. Nature 420, 885-891 (2002).

2.      Rongbin Z., et al. Recognition of double-stranded RNA by TLR3 induces severe small intestinal injury in mice. The Journal of Immunology 178, 4548–4556 (2007).

3. Karen A., et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. Journal of Experimental Medicine 205, 2609-2621 (2008).