title: Toll-like receptor 4 and high-mobility group box 1 are critical mediators of tissue injury and survival in a mouse model for heatstroke.
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.
authors.affiliation: Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia. mohammed.dehbi@dasmaninstitute.org
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dehbi
authors.forename: Taher
authors.initials: T
authors.lastname: Uzzaman
authors.forename: Engin
authors.initials: E
authors.lastname: Baturcam
authors.forename: Abdelmoneim
authors.initials: A
authors.lastname: Eldali
authors.forename: Wilhelmina
authors.initials: W
authors.lastname: Ventura
authors.forename: Abderrezak
authors.initials: A
authors.lastname: Bouchama
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001831:Body Temperature; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D018883:Heat Stroke / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D006358:Hot Temperature / Q000009:adverse effects; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4