NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1β-mediated neuroinflammation

Abstract

Background Patients 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. Methods In 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. Results Prior 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. Conclusions Based 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.

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…This activation results in the production of pro-inflammatory cytokines, e.g., IL-6, IL-1β, and tumor necrosis factor (TNF)-α ( 31 , 33 , 35 , 50 ). Moreover, the animal models of heat stroke have shown that, when LPS is present, NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasomes are activated and drive neuroinflammation ( 81 ). A vicious cycle centered around intestinal injury ensues in heat stroke involving the release of nitric oxide, the leakage of gut-related endotoxins, and increased production of inflammatory cytokines (e.g., TNF-α, IL-1β, and IFN-γ) ( 35 ).…”

“…Critically, normalization of the core temperature does not necessarily inhibit the systemic inflammatory response in heat stroke ( 1 ). Researchers have thus suggested and tried the modulation of the inflammatory response as a form of heat stroke treatment and prophylaxis, including with the administration of IL-1 receptor antagonists ( 81 , 84 ), corticosteroids ( 60 , 85 ), activated protein C ( 86 ), and the inhibition of nuclear factor-kB activity ( 1 ). Others have used oleoylethanolamide to inhibit LPS-induced TLR-4 stimulation of the immune response ( 50 , 87 ).…”

Pathophisiology of the gastrointestinal tract in general unintentional overheating of the body (scientific and literature review)

“…Ішемія/реперфузія (І/R) призводить до значного зниження клітинного та мітохондріального дихання з подальшою активацією апоптозу клітин у тканинах кишечника навіть після 30-хвилинної неоклюзійної гіпотензії [25]. Більше того, поліморфноклітинні нейтрофіли самі по собі генерують реактивні кисневі метаболіти та безпосередньо взаємодіють з ендотеліальними клітинами судин, що призводить до мікроциркуляторних порушень у кишечнику, а незабаром і до втрати бар'єрної функції [33].…”

P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine

“…The activation of P2X7R can promote the formation of NLRP3 inflammasome [ 16 , 17 ], which is an intracellular multimeric protein complex that initiates inflammatory response and cell death (pyroptosis and apoptosis) by activating its effector caspase-1 [ 18 – 20 ]. The active caspase-1 facilitates the production of proinflammatory cytokines IL-1β and IL-18 [ 21 – 23 ], and activates pyroptosis-related protein Gasdermin D (GSDMD) and apoptosis-related protein caspase-3 [ 24 – 26 ]. This may lead to gliosis, neuronal loss and white matter damage, consequently leading to cognitive impairment [ 27 ].…”