Abstract
BackgroundPatients with prior illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke.MethodsIn this study, we used a classic animal heat stroke model. Prior infection was mimicked by using lipopolysaccharide (LPS) or lipoteichoic acid (LTA) injection before heat stroke (LPS/LTA 1 mg/kg). Mice survival analysis curve and core temperature (TC) elevation curve were produced. NLRP3 inflammasome activation was measured by using real-time PCR and Western blot. Mice hypothalamus was dissected and neuroinflammation level was measured. To further demonstrate the role of NLRP3 inflammasome, Nlrp3 knockout mice were used. In addition, IL-1β neutralizing antibody was injected to test potential therapeutic effect on heat stroke.ResultsPrior infection simulated by LPS/LTA injection resulted in latent inflammation status presented by high levels of cytokines in peripheral serum. However, LPS/LTA failed to cause any change in animal survival rate or body temperature. In the absence of LPS/LTA, heat treatment induced heat stroke and animal death without significant systemic or neuroinflammation. Despite a decreased level of IL-1β in hypothalamus, Nlrp3 knockout mice demonstrated no survival advantage under mere heat exposure. In animals with prior infection, their heat tolerance was severely impaired and NLRP3 inflammasome induced neuroinflammation was detected. The use of Nlrp3 knockout mice enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1β production with prior infection condition. Furthermore, IL-1β neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke.ConclusionsBased on the above results, NLRP3/IL-1β induced neuroinflammation might be an important mechanistic factor in heat stroke pathology, especially with prior infection. IL-1β may serve as a biomarker for heat stroke severity and potential therapeutic method.
Highlights
Heat stroke is characterized clinically by severe hyperthermia and defined as a core temperature of > 40.5 °C
Pro-inflammatory cytokines including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) are elevated in both infection and heat stroke, suggesting infection might prime a latent immune response that is synergistically driven by heat challenge and promoted severe pathology [7]
This study aimed to investigate the effect of central nervous system (CNS) NLR family pyrin domain containing 3 (NLRP3) inflammasome in heat stroke in endotoxemic mice
Summary
Heat stroke is characterized clinically by severe hyperthermia and defined as a core temperature of > 40.5 °C. Pre-existing illness caused by Gram-negative (G-) bacteria (LPS) or Gram-positive (G+) bacteria (LTA) was believed to play a crucial role in heat tolerance impairment and increase susceptibility to heat stroke [5]. Prior infection is known to impair heat tolerance, potentially by pre-inducing a febrile and immune compromised state [6]. Pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α are elevated in both infection and heat stroke, suggesting infection might prime a latent immune response that is synergistically driven by heat challenge and promoted severe pathology [7]. Multiple ideas have been put forth as to how pre-existing endotoxemia compromises heat tolerance and the role of thermal regulation, and deregulation is increasingly appreciated. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke
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