Perioperative neurocognitive disorders (PNDs) are frequent complications associated with cognitive impairment during the perioperative period, including acute postoperative delirium (PD) and long-lasting postoperative cognitive dysfunction (POCD), which were once considered two distinguishing (Evered et al., 2018). Some PNDs patients develop Alzheimer’s disease (AD; Vanderweyde et al., 2010), and preclinical AD patients tend to suffer from PNDs when exposed to anesthesia and surgery (Evered et al., 2016). There are several risk factors for PNDs, including increasing age, surgical trauma, anesthetics, poor health, lower education levels, pain, and some preconditions, such as anticholinergic medications, mental disease, and abnormal sleep rhythm(Kalisvaart et al., 2006; Kotekar et al., 2018; Ni et al., 2019; Wei et al., 2019). Among the potential risk factors, advanced age is a relatively definite risk factor. With the aging of the population and the increased demand for surgery, it is foreseeable that the incidence of PNDs will increase (Wei et al., 2019) and lead to increased morbidity, mortality, and a heavier social burden (Androsova et al., 2015). Therefore, examination of PNDs pathogenesis and effective treatment strategies are important.

The underlying mechanism of PNDs has not been fully elucidated. Many recent clinical trials and experiments have proposed several hypotheses, including neuroinflammation (Cibelli et al., 2010; Safavynia and Goldstein, 2018; Xiang et al., 2019), synapse dysfunction (Xu et al., 2017), amyloid beta (Aβ) accumulation, and tau protein phosphorylation (Yu et al., 2020), which indicate that a common pathogenic pathway exists between PNDs and neurodegenerative disorders, especially AD. Among these, neuroinflammation may be the highlighted mechanism of PNDs (Cibelli et al., 2010; Safavynia and Goldstein, 2018; Xiang et al., 2019). This theory includes three parts: peripheral inflammation, central inflammation, and the link between these conditions. The elevation of proinflammatory cytokines in the periphery and cerebrospinal fluid is positively related to PNDs (Liu et al., 2018). Patients with high interleukin (IL)-1β in presurgical cerebrospinal fluid (CSF) tend to suffer from PNDs (Ji et al., 2013). Damaged peripheral cells caused by surgery release high molecular group box 1 protein (HMGB1), which is a type of damage-associated molecular pattern (DAMP) that may be sensed by Toll-like receptors (TLRs; Lotze and Tracey, 2005). HMGB1 is also increased in the hippocampus after surgery and may contribute to changes in the blood–brain barrier (BBB; He et al., 2012). The nuclear factor (NF)-κB signaling pathway is triggered and upregulates the release of cytokines [(TNF)-α, IL-1β, and IL-6], which maintain peripheral inflammation (Li et al., 2022). Changes in the permeability or integrity of the BBB may be the bridge between peripheral inflammation and neuroinflammation (Li et al., 2022). Notably, intestinal inflammation induces neuroinflammation via a certain mechanism and ultimately contributes to cognitive impairment (He et al., 2021). The imbalance of gut microbiota caused by surgery or anesthesia contributes to the development of PNDs (Lian et al., 2021).

Pyroptosis is an inflammatory form of programmed cell death, that leads to plasma membrane disruption, potassium efflux, and IL-1β and IL-18 release by canonical or noncanonical pathways. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the canonical pyroptosis pathway, which is associated with neurodegenerative diseases, such as AD, Parkinson’s disease, and epilepsy (Moujalled et al., 2021; Xia et al., 2021), and is a pivotal role in PNDs (Zhang et al., 2021b). In recent studies, NLRP3 is significantly increased in the PNDs mouse model (Zhang et al., 2021b) and is associated with isoflurane-induced cognitive impairment (Wang et al., 2018; Yin et al., 2018). Inhibiting NLRP3 and caspase-1 (its downstream target) with MCC950 and AC-YVAD-CMK, respectively, reduced the expression of IL-1β and attenuated PNDs (Fan et al., 2018; Fu et al., 2020; Zhang Z. et al., 2021). It seems that NLRP3 could lead PNDs directly.

At the same time, NLRP3 has a strong relationship with the risk factors for PNDs. NLRP3 inflammasome increases in the hippocampus of aged rats (Wang et al., 2022). Pain contributes to PNDs (Chi et al., 2013), the NLRP3 inflammasome mediates postoperative mechanical pain, and knockout of NLRP3 reduced mechanical hypersensitivity and pain-like behavior in mice (Cowie et al., 2019). The NLRP3 inflammasome is also involved in abnormal sleep rhythm. The expression of the NLRP3 inflammasome (NLRP3, ASC, and active caspase-1) increased in the hippocampal CA1 region of mice in the sleep deprivation group, and this effect could be reversed by sleep recovery (Fan et al., 2021). NLRP3 inflammasome activation could be induced by Aβ accumulation and lead to Tau hyperphosphorylation, which may verify the role of the NLRP3 inflammasome in AD pathogenesis (Ising et al., 2019). In addition, colitis could upregulate neuroinflammation, Aβ deposition, and cognitive impairment, but this effect could be mitigated by kickout of NLRP3 (He et al., 2021).

Therefore, NLRP3 not only induces PNDs directly but also promotes risk factors for PNDs. The NLRP3 inflammasome plays a potential role in the pathogenesis of PNDs, and any treatment inhibiting the NLRP3 inflammasome pathway may be an effective strategy to treat PNDs. The present review summarizes recent studies and systematically describes the pathogenesis of NLRP3 activation and regulation and potential therapeutics targeting NLRP3 inflammasomes in PNDs patients.

The NLRP3 inflammasome is a multiprotein complex that includes the NLRP3 protein, apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. The NLRP3 protein (the sensor of the NLRP3 inflammasome) is a pattern recognition receptor (PRR) that consists of an amino-terminal pyrin domain (PYD), a central NACHT domain (which has ATPase activity), and a carboxy-terminal LRR domain. ASC consists of an N-terminal PYD and a C-terminal caspase-recruitment domain (CARD), and pro-caspase-1 has an N-terminal CARD. After recognizing the stimulus, NLRP3 oligomerizes and recruits ASC via a PYD domain interaction, and then ASC recruits pro-caspase-1 via a CARD domain interaction and induces the self-cleavage of pro-caspase-1 (Swanson et al., 2019). The active form of caspase cleaves pro-IL-1β and pro-IL-18 into their mature forms (Lawlor and Vince, 2014). This step is the assembly process and effect of the NLRP3 inflammasome. There are potential therapeutic strategies for each step in this process.

There are three kinds of NLRP3 inflammasome activation pathways: the canonical, noncanonical, and alternative NLRP3 inflammasome pathways, as shown in Figure 1. The canonical pathway is also known as the two-signal model (Huang et al., 2021). The first signal from TLRs or cytokine receptors induces NLRP3 and pro-IL-1β expression via NF-κB activation and is the priming of the NLRP3 inflammasome. The second signal is triggered by microbial products or danger signals, such as ATP, pore-forming toxins, and viral RNA (Bauernfeind et al., 2009; He et al., 2016; Xing et al., 2017). Once these stimuli are sensed, the assembly and activation of the NLRP3 inflammasome is initiated as described above. Several events are regarded as activation signals of the NLRP3 inflammasome, including mitochondrial dysfunction (Zuo et al., 2020), mitochondrial DNA (mtDNA) synthesis (Zhong et al., 2018), reactive oxygen species (ROS) (Wei et al., 2019), ionic flux [potassium efflux (Muñoz-Planillo et al., 2013), calcium influx (Murakami et al., 2012), and chloride efflux (Tang et al., 2017; Swanson et al., 2019)], trans-Golgi disassembly (Gaidt et al., 2016), and plasma membrane rupture (Beckwith et al., 2020). In contrast to the canonical pathway, the noncanonical pathway is dependent on caspase-4/5 (mouse caspase-11), which may be converted to an active state via direct binding to LPS and lipid A. Active caspase-4/5/11 also induces pyroptosis via pore formation, which is characteristic of GSDMD (Shi et al., 2014). Plasma membrane rupture and K⁺ efflux further trigger activation of the NLRP3 inflammasome. The alternative pathway is completed by TLR4-TRIF-RIPK1-FADD-CASP8 signaling, which responds to LPS and ultimately causes IL-1β release (Gaidt et al., 2016). Apolipoprotein C3 (ApoC3) primes the alternative pathway via TLR2/4-SCIMP-Lyn-Syk-TRPM2-CASP8 in human monocytes. However, alternative NLRP3 inflammasome activation does not induce ASC speck formation or pyroptosis (Zewinger et al., 2020). Therefore, canonical and noncanonical NLRP3 inflammasome activation are described in this article because they induce GSDMD to execute pyroptosis.

GSDMD is the substrate of caspase-1/4/5/11 and may be cleaved to form the gasdermin-N-terminal and gasdermin-C-terminal. The latter autoinhibits the gasdermin-N-terminal, which is the functional segment that contributes to pyroptosis (Shi et al., 2017). Once the interaction of these two segments is disrupted by caspase, the GSDMs are activated (Shi et al., 2015). Therefore, there are two ways in which GSDMs are activated. First, proteases cleave and release the NT active domain, and second, the CT domain is mutated, which diminishes the negative regulation of the NT domain by the CT domain (Liu X. et al., 2021). Once the GSDMD-N-terminal is released, it oligomerizes in the membrane to form pores that permit the release of cytokines, such as IL-1β, and lead to ion flux, such as calcium and potassium, which may further prompt activation of the NLRP3 inflammasome (Liu et al., 2016; Fischer et al., 2021). GSDMD-induced pyroptosis contributes to cognitive disorders caused by sevoflurane neurotoxicity (Wen-Yuan et al., 2022). An increasing number of studies have shown that other members of the gasdermin family (GSDMA3, GSDMB (Zhou et al., 2020), GSDMC (Hou et al., 2020), and GSDME (Rogers et al., 2017; Wang Y. et al., 2017) contribute to pyroptosis via other caspases or molecules (Huang et al., 2021).

Based on the compound of NLRP3 and its mechanism, any blocking the assembly process of the NLRP3 inflammasome, inhibiting the activation signals of the NLRP3 inflammasome, and decreasing and dysfunction of GSDMD (downstream of NLRP3 inflammasome) could relieve PNDs.

PTM of the NLRP3 inflammasome, including ubiquitination, phosphorylation, small ubiquitin-like modifier (SUMO) ylation, alkylation, and S-nitrosylation, is involved in regulating inflammasome activation (Tang T. et al., 2021). PTMs may occur at any step in the pyroptosis pathway of proteins, such as NLRP3 and gasdermins (Fischer et al., 2021). Different PTMs do not work independently but interact with each other. The mechanism is very complex. We used the NLRP3 inflammasome as an example to briefly introduce the effects of PTMs, as shown in Figure 2. The molecule that promotes the activation of NLRP3 could induce PNDs, while the other inactive NLRP3 may be a potential treatment strategy for PNDs.

NLRP3 inflammasome activation and the induction of canonical pyroptosis are related to PNDs. Any blockade of the pathway, such as upstream of the NLRP3 inflammasome, the formation of the NLRP3 inflammasome, and its downstream factors (GSDMD, IL-1β, and IL-18), inhibits pyroptosis and may reverse the progression of PNDs. We described some drugs, chemicals, new materials, and technologies to potentially treat the activation of NLRP3 in PNDs.

PNDs are frequent complications with cognitive impairment that is identified during the perioperative period and may be induced by surgery or anesthetic. PNDs occur more commonly in elderly patients. With the aging of the population and the increased demand for surgery, the foreseeable increase in PNDs will lead to increased morbidity, mortality, and a heavier burden on families and society (Androsova et al., 2015; Wei et al., 2019). The underlying mechanisms are complex and unclear, but inflammation may be the key mechanism of PNDs (Cibelli et al., 2010). Pyroptosis is an inflammatory form of programmed cell death that contributes to neuronal death, is associated with neurodegenerative diseases, such as AD and Parkinson’s disease, and is related to PNDs. NLRP3 inflammasome-induced canonical pyroptosis may be associated with the mechanism of PNDs (Zhang et al., 2021b). The present study primarily demonstrated NLRP3 inflammasome-related neuroinflammation in PNDs and the components and mechanisms of NLPR3 induced pyroptosis. The review introduced the PTMs of NLRP3 and suggested prevention strategies (drugs and new technology) by targeting NLRP3 inflammasomes in future studies of PNDs.

The NLRP3 inflammasome is a multiprotein complex that includes NLRP3 protein, ASC, and pro-caspase-1 (Swanson et al., 2019). There are three kinds of NLRP3 inflammasome activation pathways, as presented in Figure 1. There are several targets that interfere with NLRP3-dependent pyroptosis, including upstream of the NLRP3 inflammasome, the inflammasome itself, and downstream of the inflammasome. NF-κB is a critical upstream target of the NLRP3 inflammasome (Bauernfeind et al., 2009). Activation of the NF-κB pathway upregulates the transcription of NLRP3 and IL-1β, which are necessary for canonical NLRP3 pathway activation (Bauernfeind et al., 2009). Mitochondrial dysfunction (Zhou et al., 2011; Zuo et al., 2020), ionic flux (Muñoz-Planillo et al., 2013; Swanson et al., 2019), trans-Golgi disassembly (Gaidt et al., 2016), and plasma membrane rupture (Schorn et al., 2011) are also likely upstream events of the NLRP3 inflammasome. Inhibition of these pathways also effectively downregulates the expression of the NLRP3 inflammasome. However, using these pathways as treatment targets may result in a lack of specificity because they also participate in other signaling pathways. Targeting the assembly of the inflammasome is a highly specific strategy, but there are few definite drugs at present. Notably, GSDMD is an indispensable target of pyroptosis and may be a specific target to control pyroptosis.

PTMs are an emerging and potential research field because they modify multiple proteins. PTMs occur at many steps in pyroptosis pathway proteins, such as NLRP3 and gasdermins (Fischer et al., 2021). We used the NLRP3 inflammasome as an example to briefly introduce PTMs, including ubiquitination, phosphorylation, SUMOylation alkylation, and S-nitrosylation. Some molecules that influence the PTMs of NLRP3 are presented in Figure 2. Different PTMs work interactively, and inactivating NLRP3 may be a potential treatment strategy for PNDs. The specific functional site and mechanisms that may be the target of PNDs need further research.

Based on current knowledge of NLPR3-induced pyroptosis, we briefly listed some drugs that decrease pyroptosis and release PNDs, focusing on upstream of the NLRP3 inflammasome, the inflammasome itself, and downstream of the inflammasome (Table 1). Some new technologies are emerging, including gene editing, TPD, and nanotechnology. TPD performs in a highly specific and advanced manner using the PTM mechanism to regulate the degradation of particular proteins. Nanotechnology is a rapidly emerging program that is applied in tissue regeneration, drug delivery, and pharmaceuticals (Sridhar et al., 2015). Various NPs or NMs have been synthesized to exploit the existing physiological mechanisms of disease treatments by carrying the drug through the BBB to provide a high concentration at the target receptor and prolonging the drug effect time. Although there is less research on the application of new technologies in PNDs, these technologies are widely used in the research of cancer and AD (Xiao et al., 2016; Dale and Cheng, 2021; Ding et al., 2021). Therefore, their use for PNDs treatment is highly likely in the near future.

In conclusion, NLRP3 inflammasomes induce the canonical pyroptosis pathway, which contributes to PNDs and is an effective therapeutic target for the treatment of PNDs. Based on the mechanisms of the NLRP3 pathway, any activation of NLRP3 upstream promoting factors, the NLRP3 inflammasome, and its downstream factors (GSDMD, IL-1β, and IL-18) may be treatment targets for PNDs. The current review systematically illustrated some drugs, chemicals, new materials, and technologies that inhibit the activation of NLRP3 and may be used to treat PNDs patients in the future.

FB conceived the original idea. JL wrote the manuscript with support from LL, JH, and JX. All authors contributed to the article and approved the submitted version.

The study was supported by Experimental Animal of Public Welfare Research Project of Zhejiang Province (grand number LGD20H090006, FB) and The Medical Scientific Research Foundation of Zhejiang Province (grand number 2020KY626, FB), China.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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