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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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Acute but not sustained peritoneal inflammation in tlr3−/− mice after CLP or gut ischemia. (A–F) At 6 and 24 h after CLP surgery, WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. (G) WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. The data represent means ± SEM obtained from three independent experiments for CLP and two independent experiments for gut ischemia. *, P < 0.05 compared with WT groups. nd, not detected.
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fig4: Acute but not sustained peritoneal inflammation in tlr3−/− mice after CLP or gut ischemia. (A–F) At 6 and 24 h after CLP surgery, WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. (G) WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. The data represent means ± SEM obtained from three independent experiments for CLP and two independent experiments for gut ischemia. *, P < 0.05 compared with WT groups. nd, not detected.

Mentions: We next assessed whether the generation of inflammatory cytokines and chemokines differed between WT and tlr3−/− mice during septic inflammatory responses in the peritoneal cavity. At 6 h after CLP surgery, peritoneal levels of IFN-β were significant reduced in the tlr3−/− group compared with the WT group (Fig. 4 A). The peritoneal levels of CCL5 (Fig. 4 B) and CXCL10 (Fig. 4 C) were higher in the tlr3−/− group compared with the WT group at this time, but levels of TNF-α (Fig. 4 D), CCL3 (Fig. 4 E), and MIP-2 (Fig. 4 F) were similar in the two groups of mice at 6 h after CLP. At 24 h after CLP surgery, all peritoneal levels of the cytokines and chemokines were significantly reduced in the tlr3−/− CLP group versus the WT CLP group (Fig. 4, A–F).


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)

Acute but not sustained peritoneal inflammation in tlr3−/− mice after CLP or gut ischemia. (A–F) At 6 and 24 h after CLP surgery, WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. (G) WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. The data represent means ± SEM obtained from three independent experiments for CLP and two independent experiments for gut ischemia. *, P < 0.05 compared with WT groups. nd, not detected.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571935&req=5

fig4: Acute but not sustained peritoneal inflammation in tlr3−/− mice after CLP or gut ischemia. (A–F) At 6 and 24 h after CLP surgery, WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. (G) WT and tlr3−/− peritoneal cytokine and chemokine concentrations were measured by ELISA. The data represent means ± SEM obtained from three independent experiments for CLP and two independent experiments for gut ischemia. *, P < 0.05 compared with WT groups. nd, not detected.
Mentions: We next assessed whether the generation of inflammatory cytokines and chemokines differed between WT and tlr3−/− mice during septic inflammatory responses in the peritoneal cavity. At 6 h after CLP surgery, peritoneal levels of IFN-β were significant reduced in the tlr3−/− group compared with the WT group (Fig. 4 A). The peritoneal levels of CCL5 (Fig. 4 B) and CXCL10 (Fig. 4 C) were higher in the tlr3−/− group compared with the WT group at this time, but levels of TNF-α (Fig. 4 D), CCL3 (Fig. 4 E), and MIP-2 (Fig. 4 F) were similar in the two groups of mice at 6 h after CLP. At 24 h after CLP surgery, all peritoneal levels of the cytokines and chemokines were significantly reduced in the tlr3−/− CLP group versus the WT CLP group (Fig. 4, A–F).

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