Hypercapnia induces IL-1β overproduction via activation of NLRP3 inflammasome: implication in cognitive impairment in hypoxemic adult rats

Abstract

BackgroundCognitive impairment is one of common complications of acute respiratory distress syndrome (ARDS). Increasing evidence suggests that interleukin-1 beta (IL-1β) plays a role in inducing neuronal apoptosis in cognitive dysfunction. The lung protective ventilatory strategies, which serve to reduce pulmonary morbidity for ARDS patients, almost always lead to hypercapnia. Some studies have reported that hypercapnia contributes to the risk of cognitive impairment and IL-1β secretion outside the central nervous system (CNS). However, the underlying mechanism of hypercapnia aggravating cognitive impairment under hypoxia has remained uncertain. This study was aimed to explore whether hypercapnia would partake in increasing IL-1β secretion via activating the NLRP3 (NLR family, pyrin domain-containing 3) inflammasome in the hypoxic CNS and in aggravating cognitive impairment.MethodsThe Sprague-Dawley (SD) rats that underwent hypercapnia/hypoxemia were used for assessment of NLRP3, caspase-1, IL-1β, Bcl-2, Bax, and caspase-3 expression by Western blotting or double immunofluorescence, and the model was also used for Morris water maze test. In addition, Z-YVAD-FMK, a caspase-1 inhibitor, was used to treat BV-2 microglia to determine whether activation of NLRP3 inflammasome was required for the enhancing effect of hypercapnia on expressing IL-1β by Western blotting or double immunofluorescence. The interaction effects were analyzed by factorial ANOVA. Simple effects analyses were performed when an interaction was observed.ResultsThere were interaction effects on cognitive impairment, apoptosis of hippocampal neurons, activation of NLRP3 inflammasome, and upregulation of IL-1β between hypercapnia treatment and hypoxia treatment. Hypercapnia + hypoxia treatment caused more serious damage to the learning and memory of rats than those subjected to hypoxia treatment alone. Expression levels of Bcl-2 were reduced, while that of Bax and caspase-3 were increased by hypercapnia in hypoxic hippocampus. Hypercapnia markedly increased the expression of NLRP3, caspase-1, and IL-1β in hypoxia-activated microglia both in vivo and in vitro. Pharmacological inhibition of NLRP3 inflammasome activation and release of IL-1β might ameliorate apoptosis of neurons.ConclusionsThe present results suggest that hypercapnia-induced IL-1β overproduction via activating the NLRP3 inflammasome by hypoxia-activated microglia may augment neuroinflammation, increase neuronal cell death, and contribute to the pathogenesis of cognitive impairments.

Hypercapnia intensifies cerebral hypoxia via increasing cerebral oxygen extraction ratio: implication in neuroinflammation in hypoxemic adult rats

“…The present rat and cell models of hypercapnia/hypoxemia were established as described in our previous study. In the models, PO 2 levels of the arterial blood and culture supernatant were maintained at 55-60 mmHg and pH levels of the arterial blood and culture supernatant at 7.20-7.25 [9]. These are consistent with the change of hypoxemia and permissive hypercapnia in ARDS [25][26][27][28].…”

“…We reporeted in our previous study that hypercapnia-induced NLRP3 inflammasome activation in hypoxia-activated microglia could upregulate the expression of IL-1β. It is well documented that IL-1β promotes a cascade of inflammatory response in the central nervous system that can lead to the aggravation of neuronal injury [9]. Under hypoxic conditions, ROS is known to be critical for NLRP3 inflammasome activation [29][30][31].…”

“…All rats were fasted with access to water overnight before the experiments. The rat model of hypercapnia/hypoxemia was established as described in our previous study [9]. Briefly, the rats were anesthetized with pentobarbital sodium followed by mechanical ventilation.…”

“…The ventilation strategy will certainly result in hypercapnia, which is called "permissive hypercapnia" [7,8]. Our previous study found that increase neuronal death and aggravate the cognitive function of hypoxic adult rats [9]. However, the underlying mechanism has remained unclear.…”

Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy: implication in neuroinflammation in hypoxemic adult rats

“…The ventilation strategy will certainly result in hypercapnia, which is called "permissive hypercapnia" [7,8]. Our previous study found that hypercapnia could induce IL-1β overproduction in hypoxia-activated microglia [9]. However, the underlying mechanism has remained unclear.…”