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

Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL - J. Exp. Med. (2008)

Bottom Line: We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus.Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages.In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. kcavassa@med.umich.edu

ABSTRACT
Ligands from dying cells are a source of Toll-like receptor (TLR) activating agents. Although TLR3 is known to respond to RNA from necrotic cells, the relative importance of this response in vivo during acute inflammatory processes has not been fully explored. We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus. In TLR3-deficient mice, increased chemokine/cytokine levels and neutrophil recruitment characterized the initial inflammatory responses in both injury models. However, the levels of inflammatory chemokines and tumor necrosis factor alpha quickly returned to baseline in tlr3(-/-) mice, and these mice were protected from the lethal effects of sustained inflammation. Macrophages from tlr3(-/-) mice responded normally to other TLR ligands but did not respond to RNA from necrotic neutrophils. Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages. In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality. Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation.

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tlr3−/− mice are resistant to lethality after CLP surgery and exhibit less tissue damage after gut ischemia. (A) Septic peritonitis was induced by CLP in WT (n = 20) and tlr3−/− (n = 17) mice. Mortality was monitored every 24 h for 8 d. ***, P < 0.0001 compared with the WT group. (B) Representative Masson's trichrome staining of cecum at 24 h after gut ischemia induced by total cecal ligation (n = 6). Bars, 100 μm.
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fig3: tlr3−/− mice are resistant to lethality after CLP surgery and exhibit less tissue damage after gut ischemia. (A) Septic peritonitis was induced by CLP in WT (n = 20) and tlr3−/− (n = 17) mice. Mortality was monitored every 24 h for 8 d. ***, P < 0.0001 compared with the WT group. (B) Representative Masson's trichrome staining of cecum at 24 h after gut ischemia induced by total cecal ligation (n = 6). Bars, 100 μm.

Mentions: To evaluate the contribution of TLR3 activation on the mortality induced by septic peritonitis, we monitored survival rates in tlr3−/− and WT mice for 8 d after CLP. The tlr3−/− animals were significantly protected from sepsis-induced lethality (Fig. 3 A). The data show that ∼80% of WT mice were dead at 4 d after CLP surgery, whereas ∼80% of tlr3−/− mice were alive at day 8 after surgery. Mortality in the CLP model is caused by multiorgan failure (14), including ischemic injury to the bowel. In addition to the septic injury, we examined the role of TLR3 in ischemic injury to the gastrointestinal tract induced by complete ligation of the cecum. As shown in Fig. 3 B, complete ligation of the cecum without punctures for 24 h in WT mice caused severe necrotic injury to this portion of the bowel, characterized by the near total loss of tissue architecture and integrity. In contrast, the same procedure in tlr3−/− mice was associated with markedly less destruction to the architecture of the cecum and the cell infiltrate, and the contents of the cecum were still apparent in this organ, suggesting that reduced intralumen of its contents had leaked into the peritoneal cavity. Compared with WT mice, tlr3−/− mice showed significantly reduced levels of alanine aminotransferase, aspartate aminotransferase (AST), bilirubin, and lactic acid dehydrogenase (LDH) after 6 and 24 h following CLP surgery, and at 24 h after total cecal ligation (Fig. S2, available at http://www.jem.org/cgi/content/full/jem.20081370/DC1). Collectively, these findings are consistent with the concept that TLR3 activation contributes to the magnitude of the inflammatory response evoked by both septic and necrotic processes in the damaged gastrointestinal tract.


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

Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL - J. Exp. Med. (2008)

tlr3−/− mice are resistant to lethality after CLP surgery and exhibit less tissue damage after gut ischemia. (A) Septic peritonitis was induced by CLP in WT (n = 20) and tlr3−/− (n = 17) mice. Mortality was monitored every 24 h for 8 d. ***, P < 0.0001 compared with the WT group. (B) Representative Masson's trichrome staining of cecum at 24 h after gut ischemia induced by total cecal ligation (n = 6). Bars, 100 μm.
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getmorefigures.php?uid=PMC2571935&req=5

fig3: tlr3−/− mice are resistant to lethality after CLP surgery and exhibit less tissue damage after gut ischemia. (A) Septic peritonitis was induced by CLP in WT (n = 20) and tlr3−/− (n = 17) mice. Mortality was monitored every 24 h for 8 d. ***, P < 0.0001 compared with the WT group. (B) Representative Masson's trichrome staining of cecum at 24 h after gut ischemia induced by total cecal ligation (n = 6). Bars, 100 μm.
Mentions: To evaluate the contribution of TLR3 activation on the mortality induced by septic peritonitis, we monitored survival rates in tlr3−/− and WT mice for 8 d after CLP. The tlr3−/− animals were significantly protected from sepsis-induced lethality (Fig. 3 A). The data show that ∼80% of WT mice were dead at 4 d after CLP surgery, whereas ∼80% of tlr3−/− mice were alive at day 8 after surgery. Mortality in the CLP model is caused by multiorgan failure (14), including ischemic injury to the bowel. In addition to the septic injury, we examined the role of TLR3 in ischemic injury to the gastrointestinal tract induced by complete ligation of the cecum. As shown in Fig. 3 B, complete ligation of the cecum without punctures for 24 h in WT mice caused severe necrotic injury to this portion of the bowel, characterized by the near total loss of tissue architecture and integrity. In contrast, the same procedure in tlr3−/− mice was associated with markedly less destruction to the architecture of the cecum and the cell infiltrate, and the contents of the cecum were still apparent in this organ, suggesting that reduced intralumen of its contents had leaked into the peritoneal cavity. Compared with WT mice, tlr3−/− mice showed significantly reduced levels of alanine aminotransferase, aspartate aminotransferase (AST), bilirubin, and lactic acid dehydrogenase (LDH) after 6 and 24 h following CLP surgery, and at 24 h after total cecal ligation (Fig. S2, available at http://www.jem.org/cgi/content/full/jem.20081370/DC1). Collectively, these findings are consistent with the concept that TLR3 activation contributes to the magnitude of the inflammatory response evoked by both septic and necrotic processes in the damaged gastrointestinal tract.

Bottom Line: We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus.Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages.In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. kcavassa@med.umich.edu

ABSTRACT
Ligands from dying cells are a source of Toll-like receptor (TLR) activating agents. Although TLR3 is known to respond to RNA from necrotic cells, the relative importance of this response in vivo during acute inflammatory processes has not been fully explored. We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus. In TLR3-deficient mice, increased chemokine/cytokine levels and neutrophil recruitment characterized the initial inflammatory responses in both injury models. However, the levels of inflammatory chemokines and tumor necrosis factor alpha quickly returned to baseline in tlr3(-/-) mice, and these mice were protected from the lethal effects of sustained inflammation. Macrophages from tlr3(-/-) mice responded normally to other TLR ligands but did not respond to RNA from necrotic neutrophils. Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages. In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality. Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation.

Show MeSH
Related in: MedlinePlus