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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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Anti-TLR3 antibody markedly reduced cecal damage induced by gut ischemia and enhanced survival after the induction of severe sepsis. (A and B) Representative histological sections from WT mice that received either IgG (A) or anti-TLR3 (B) antibody during gut ischemia. The inset in A is a representative histological cross section of cecum from a naive WT mouse. Bars, 100 μm. (C) At 24 h after surgery, serum from WT mice subjected to cecal ischemia and either IgG or anti-TLR3 antibody treatments (n = 4 mice per group) were analyzed for AST and LDH. The data are means ± SEM. *, P < 0.05 compared with the IgG group. (D) WT mice received 3 mg of anti-TLR3 antibody or isotype control at 6 and 24 h after CLP surgery, and the survival rates were monitored for 54 h (n = 7 for the anti-TLR3 antibody group; n = 8 for the IgG group).
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fig8: Anti-TLR3 antibody markedly reduced cecal damage induced by gut ischemia and enhanced survival after the induction of severe sepsis. (A and B) Representative histological sections from WT mice that received either IgG (A) or anti-TLR3 (B) antibody during gut ischemia. The inset in A is a representative histological cross section of cecum from a naive WT mouse. Bars, 100 μm. (C) At 24 h after surgery, serum from WT mice subjected to cecal ischemia and either IgG or anti-TLR3 antibody treatments (n = 4 mice per group) were analyzed for AST and LDH. The data are means ± SEM. *, P < 0.05 compared with the IgG group. (D) WT mice received 3 mg of anti-TLR3 antibody or isotype control at 6 and 24 h after CLP surgery, and the survival rates were monitored for 54 h (n = 7 for the anti-TLR3 antibody group; n = 8 for the IgG group).

Mentions: Given that the genetic absence of TLR3 provided a dramatic protective and modulatory effect during septic and ischemic inflammatory responses in the peritoneal cavity, we next assessed whether this effect could be achieved through antibody-mediated immunoneutralization of this TLR. We therefore assessed the effect of this neutralizing anti-TLR3 antibody in WT mice subjected to total cecal ligation and CLP. IgG administration before total cecal ligation provided no protective effect, as indicated by severe tissue necrosis and marked disruption of the normal gastrointestinal architecture (Fig. 8 A, inset) observed at 24 h after surgery. In marked contrast, anti-TLR3 antibody administration preserved the histological appearance of cecal tissue analyzed in WT mice that received anti-TLR3 antibody (Fig. 8 B). The protective effect of neutralizing TLR3 receptors in this necrosis model was reflected by decreased levels of AST and LDH serum enzymes (Fig. 8 C). To examine the role of TLR3 during septic responses in WT mice, anti-TLR3 antibody was given to mice according to the following posttreatment regimens: (a) at 3 h before CLP surgery only; (b) 3 and 24 h after CLP surgery; and (c) at 6 and 24 h after CLP surgery. Although anti-TLR3 treatment regimens a and b did not affect the overall survival after CLP, anti-TLR3 treatment regimen c had a marked protective effect on the survival of WT mice after the induction of sepsis (Fig. 8 D). Collectively, these data demonstrate that the beneficial effects of TLR3 gene deficiency can be achieved via an anti-TLR3 antibody–directed approach.


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)

Anti-TLR3 antibody markedly reduced cecal damage induced by gut ischemia and enhanced survival after the induction of severe sepsis. (A and B) Representative histological sections from WT mice that received either IgG (A) or anti-TLR3 (B) antibody during gut ischemia. The inset in A is a representative histological cross section of cecum from a naive WT mouse. Bars, 100 μm. (C) At 24 h after surgery, serum from WT mice subjected to cecal ischemia and either IgG or anti-TLR3 antibody treatments (n = 4 mice per group) were analyzed for AST and LDH. The data are means ± SEM. *, P < 0.05 compared with the IgG group. (D) WT mice received 3 mg of anti-TLR3 antibody or isotype control at 6 and 24 h after CLP surgery, and the survival rates were monitored for 54 h (n = 7 for the anti-TLR3 antibody group; n = 8 for the IgG group).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2571935&req=5

fig8: Anti-TLR3 antibody markedly reduced cecal damage induced by gut ischemia and enhanced survival after the induction of severe sepsis. (A and B) Representative histological sections from WT mice that received either IgG (A) or anti-TLR3 (B) antibody during gut ischemia. The inset in A is a representative histological cross section of cecum from a naive WT mouse. Bars, 100 μm. (C) At 24 h after surgery, serum from WT mice subjected to cecal ischemia and either IgG or anti-TLR3 antibody treatments (n = 4 mice per group) were analyzed for AST and LDH. The data are means ± SEM. *, P < 0.05 compared with the IgG group. (D) WT mice received 3 mg of anti-TLR3 antibody or isotype control at 6 and 24 h after CLP surgery, and the survival rates were monitored for 54 h (n = 7 for the anti-TLR3 antibody group; n = 8 for the IgG group).
Mentions: Given that the genetic absence of TLR3 provided a dramatic protective and modulatory effect during septic and ischemic inflammatory responses in the peritoneal cavity, we next assessed whether this effect could be achieved through antibody-mediated immunoneutralization of this TLR. We therefore assessed the effect of this neutralizing anti-TLR3 antibody in WT mice subjected to total cecal ligation and CLP. IgG administration before total cecal ligation provided no protective effect, as indicated by severe tissue necrosis and marked disruption of the normal gastrointestinal architecture (Fig. 8 A, inset) observed at 24 h after surgery. In marked contrast, anti-TLR3 antibody administration preserved the histological appearance of cecal tissue analyzed in WT mice that received anti-TLR3 antibody (Fig. 8 B). The protective effect of neutralizing TLR3 receptors in this necrosis model was reflected by decreased levels of AST and LDH serum enzymes (Fig. 8 C). To examine the role of TLR3 during septic responses in WT mice, anti-TLR3 antibody was given to mice according to the following posttreatment regimens: (a) at 3 h before CLP surgery only; (b) 3 and 24 h after CLP surgery; and (c) at 6 and 24 h after CLP surgery. Although anti-TLR3 treatment regimens a and b did not affect the overall survival after CLP, anti-TLR3 treatment regimen c had a marked protective effect on the survival of WT mice after the induction of sepsis (Fig. 8 D). Collectively, these data demonstrate that the beneficial effects of TLR3 gene deficiency can be achieved via an anti-TLR3 antibody–directed approach.

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