Toll-Like Receptor 4 and High-Mobility Group Box 1 Are Critical Mediators of Tissue Injury and Survival in a Mouse Model for Heatstroke

Mohammed Dehbi, Taher Uzzaman, Engin Baturcam, Abdelmoneim Eldali, Wilhelmina Ventura, Abderrezak Bouchama

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The molecular mechanisms that initiate the inflammatory response in heatstroke and their relation with tissue injury and lethality are not fully elucidated. We examined whether endogenous ligands released by damaged/stressed cells such as high-mobility group box 1 (HMGB1) signaling through Toll-like receptor 4 (TLR4) may play a pathogenic role in heatstroke. Mutant TLR4-defective (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to heat stress in an environmental chamber pre-warmed at 43.5°C until their core temperature reached 42.7°C, which was taken as the onset of heatstroke. The animals were then allowed to recover passively at ambient temperature. A sham-heated group served as a control. Mutant mice displayed more histological liver damage and higher mortality compared with wild type mice (73% vs. 27%, respectively, P<0.001). Compared to wild type mice, mutant mice exhibited earlier plasma release of markers of systemic inflammation such as HMGB1 (206±105 vs. 63±21 ng/ml; P = 0.0018 and 209±100 vs. 46±32 ng/ml; P<0.0001), IL-6 (144±40 vs. 46±20 pg/ml; P<0.001 and 184±21 vs. 84±54 pg/ml; P = 0.04), and IL-1β (27±4 vs. 1.7±2.3 pg/ml; P<0.0001 at 1 hour). Both strains of mice displayed early release of HMGB1 into the circulation upstream of IL-1β and IL-6 responses which remained elevated up to 24 h. Specific inhibition of HMGB1 activity with DNA-binding A Box (600 μg/mouse) protected the mutant mice against the lethal effect of heat stress (60% A Box vs. 18% GST protein, P = 0.04). These findings suggest a protective role for the TLR4 in the host response to severe heat stress. They also suggest that HMGB1 is an early mediator of inflammation, tissue injury and lethality in heatstroke in the presence of defective TLR4 signaling.

Original languageEnglish
Article numbere44100
JournalPLoS One
Volume7
Issue number9
DOIs
Publication statusPublished - 4 Sep 2012
Externally publishedYes

Fingerprint

Heat Stroke
Tissue Survival
Toll-Like Receptor 4
animal models
Tissue
mice
Wounds and Injuries
Interleukin-1
Interleukin-6
Environmental chambers
heat stress
Hot Temperature
Inflammation Mediators
mutants
inflammation
interleukin-1
interleukin-6
Liver
Animals
Temperature

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Toll-Like Receptor 4 and High-Mobility Group Box 1 Are Critical Mediators of Tissue Injury and Survival in a Mouse Model for Heatstroke. / Dehbi, Mohammed; Uzzaman, Taher; Baturcam, Engin; Eldali, Abdelmoneim; Ventura, Wilhelmina; Bouchama, Abderrezak.

In: PLoS One, Vol. 7, No. 9, e44100, 04.09.2012.

Research output: Contribution to journalArticle

Dehbi, Mohammed ; Uzzaman, Taher ; Baturcam, Engin ; Eldali, Abdelmoneim ; Ventura, Wilhelmina ; Bouchama, Abderrezak. / Toll-Like Receptor 4 and High-Mobility Group Box 1 Are Critical Mediators of Tissue Injury and Survival in a Mouse Model for Heatstroke. In: PLoS One. 2012 ; Vol. 7, No. 9.
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