NLRP3 inflammasome-dependent pyroptosis is proposed to be involved in the mechanism of age-dependent isoflurane-induced cognitive impairment

Wang Z et al. recently published a paper, titled “Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment”. The finding in this paper is consistent with our previous study on NLRP3-caspase-1 pathway. Here, we propose that NLRP3 inflammasome-dependent pyroptosis may be involved in the mechanism of age-dependent isoflurane-induced cognitive impairment and discuss that inhibiting NLRP3 inflammasome activation with a novel inhibitor MCC950 may ameliorate age-dependent isoflurane-induced neuro-inflammation.


Letter to the editor
Recently, we read with great interest the article titled "Critical role of NLRP3-caspase-1 pathway in agedependent isoflurane-induced microglial inflammatory response and cognitive impairment" by Dr. Wang Z et al. [1], who concluded that NLRP3 priming status in aged mouse brain may be involved in isoflurane-induced hippocampal inflammation and cognitive impairment. We appreciate this study and would like to present our opinion on it.
The NLRP3 inflammasome-caspase-1 pathway has been implicated in several metabolic and inflammatory diseases [2,3]. It is also proposed to be a possible pathogenic mechanism for general anesthesia-induced neuro-inflammation and cognitive impairment [4,5]. We have previously shown that isoflurane induces activation of NLRP3, cleavage of caspase 1, and increase of IL-1β and TNF-α levels in the hippocampus of aging mice and supposed that inhibiting the NLRP3 inflammasome might have therapeutic merit for ameliorating general anesthesia-induced cognitive deficits [5] as cited in Wang's study. However, the selective inhibitor of NLRP3 inflammasome was lacking. Interestingly, in Wang's study, they demonstrated that treatment of Ac-YVAD-cmk, an inhibitor of NLRP3-caspase-1, reversed isoflurane-induced microglial inflammatory response and cognitive impairment in aged mice [1]. This finding is a very important evidence for supporting that NLRP3-caspase-1 pathway is involved in the mechanism of general anesthesia-induced cognitive impairment. However, Ac-YVAD-cmk is a specific inhibitor of caspase-1, not of NLRP3 inflammasome. It is uncertain whether cleavage of caspase-1 directly results from NLRP3 inflammasome activation and results in the secretion of the pro-inflammatory IL-1β and IL-18 in Wang's study [1,6,7]. The treatment of aging mice with NLRP3 inflammasome inhibitor will be needed. MCC950 is a highly potent specific NLRP3 inhibitor and was first introduced as a specific anti-inflammatory compound since 2015 [8]. The novel compound MCC950 has been clearly shown to be neuroprotective in multiple neurological disorders, including ischemic and degenerative diseases [9,10]. Although MCC950 has not been used in general anesthesia issues, we think that it is promising as a therapeutic compound for treatment of general anesthesia-induced neuro-inflammation and cognitive impairment.
Pyroptosis is a novel inflammatory form of programmed cell death that has been discovered and verified recently. This type of cell death is characterized to be NLRP3 inflammoasome-caspase-1 dependent [11][12][13]. Recent advances strongly hint that pyroptosis plays a regulatory role in many infectious and noninfectious diseases [11], and MCC950 can inhibit NLRP3 inflammasome to further prevent pyroptosis [12]. However, little is known about the functions of pyroptosis in general anesthesia-induced neurotoxicity, and thus, an effective intervention, MCC 950, is emerging. Wang's study found that isoflurane activated NLRP3-caspase-1 pathway and increased the secretion of IL-18 and IL-1β in cells pretreated with lipopolysaccharide and suggested that isoflurane induces age-related hippocampal inflammation through NLRP3caspase-1 pathway. In this regard, we present a hypothesis that pyroptosis plays a critical role in the mechanism of isoflurane-induced cognitive impairment and MCC950 inhibits the NLRP3 inflammasome-dependent pyroptosis in isoflurane anesthesia to improve the cognition.
Collectively, we present our hypothesis that NLRP3 inflammasome-dependent pyroptosis may be involved in the mechanism of age-dependent isoflurane-induced cognitive impairment, and inhibition of the NLRP3 inflammasome activation with MCC950 may ameliorate age-dependent isoflurane-induced neuro-inflammation. Future studies are needed to confirm the hypothesis.
We again compliment the authors on their excellent article and thank them for their contribution to it.
Abbreviations IL-18: Interleukin-18; IL-1β: Interleukin-1β; NLRP3: NOD-like receptor protein 3; TNF-α: Tumor necrosis factor-α Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Authors' contributions LY and JW wrote the first draft of the paper. FB and KL contributed to the writing of the paper. All authors read and approved the final manuscript.
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