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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 amplified systemic inflammatory responses and secondary tissue injury after septic peritonitis. (A–C) At 24 h after sham and CLP surgeries, chemokines were measured in lung and spleen homogenates using ELISA. Data are means ± SEM from two independent experiments (n = 4–5 mice per experiment). *, P < 0.05; and **, P < 0.01 compared with WT groups.
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fig5: TLR3 amplified systemic inflammatory responses and secondary tissue injury after septic peritonitis. (A–C) At 24 h after sham and CLP surgeries, chemokines were measured in lung and spleen homogenates using ELISA. Data are means ± SEM from two independent experiments (n = 4–5 mice per experiment). *, P < 0.05; and **, P < 0.01 compared with WT groups.

Mentions: Our data demonstrate that the absence of TLR3 had a dramatic regulatory effect on the magnitude and duration of the inflammatory response in the peritoneal cavity; therefore, we next assessed whether this modulatory effect extended to other organs. Most notably, whole lung and spleen levels of CXCL10, CCL3, and CCL2 were significantly lower in septic tlr3−/− mice when compared with septic WT mice (Fig. 5, A–C). Collectively, these data indicated that the inflammatory response in tlr3−/− mice after a septic inflammatory stimulus was restrained and regulated in a manner that markedly decreased the degree of inflammation in other organs in these mice.


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 amplified systemic inflammatory responses and secondary tissue injury after septic peritonitis. (A–C) At 24 h after sham and CLP surgeries, chemokines were measured in lung and spleen homogenates using ELISA. Data are means ± SEM from two independent experiments (n = 4–5 mice per experiment). *, P < 0.05; and **, P < 0.01 compared with WT groups.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: TLR3 amplified systemic inflammatory responses and secondary tissue injury after septic peritonitis. (A–C) At 24 h after sham and CLP surgeries, chemokines were measured in lung and spleen homogenates using ELISA. Data are means ± SEM from two independent experiments (n = 4–5 mice per experiment). *, P < 0.05; and **, P < 0.01 compared with WT groups.
Mentions: Our data demonstrate that the absence of TLR3 had a dramatic regulatory effect on the magnitude and duration of the inflammatory response in the peritoneal cavity; therefore, we next assessed whether this modulatory effect extended to other organs. Most notably, whole lung and spleen levels of CXCL10, CCL3, and CCL2 were significantly lower in septic tlr3−/− mice when compared with septic WT mice (Fig. 5, A–C). Collectively, these data indicated that the inflammatory response in tlr3−/− mice after a septic inflammatory stimulus was restrained and regulated in a manner that markedly decreased the degree of inflammation in other organs in these mice.

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