Abstract
The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an oligomeric complex that assembles in response to exogenous signals of pathogen infection and endogenous danger signals of non-microbial origin. When NLRP3 inflammasome assembly activates caspase-1, it promotes the maturation and release of the inflammatory cytokines interleukin-1B and IL-18. Aberrant activation of the NLRP3 inflammasome has been implicated in various diseases, including chronic inflammatory, metabolic, and cardiovascular diseases. The NLRP3 inflammasome can be activated through several principal mechanisms, including K+ efflux, lysosomal damage, and the production of mitochondrial reactive oxygen species. Interestingly, metabolic danger signals activate the NLRP3 inflammasome to induce metabolic diseases. NLRP3 contains three crucial domains: an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat domain. Protein–protein interactions act as a ‘pedal or brake’ to control the activation of the NLRP3 inflammasome. In this review, we present the mechanisms underlying NLRP3 inflammasome activation after induction by metabolic danger signals or via protein–protein interactions with NLRP3 that likely occur in metabolic diseases. Understanding these mechanisms will enable the development of specific inhibitors to treat NLRP3-related metabolic diseases.
Introduction
The prevalence of metabolic diseases has increased significantly in recent years. The World Health Organization has identified obesity as a significant public health problem (Chooi et al. 2019). Moreover, type 2 diabetes remains one of the top ten global causes of death, and its prevalence has increased by approximately 70% since 2000 (Lin et al. 2020). Recent studies have suggested a critical role for non-microbial sterile inflammation in progressing metabolic diseases, including obesity, insulin resistance, type 2 diabetes, hepatic steatosis, cardiovascular and joint diseases, and certain types of cancer.
The release of pro-inflammatory cytokines after abnormal inflammasome activation has been well documented in the pathogenesis of metabolic diseases (Mangan et al. 2018). The inflammasome, especially the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, has been shown to recognise danger signals of non-microbial endogenous origin (Mangan et al. 2018). Thus, it is important to understand the activators and components of inflammasomes and their activation processes to prevent and treat metabolic diseases.
NLRP3 inflammasome
The NLRP3 (also known as NACHT, LRR, and PYD domain-containing protein 3; NALP3) inflammasome is an oligomeric complex that senses pathogen-associated molecular patterns (PAMPs) in infection conditions and damage-associated molecular patterns (DAMPs) in non-microbial inflammatory conditions. The NLRP3 inflammasome complex comprises three major components: NLRP3, apoptosis speck protein with caspase recruitment (ASC), and cysteine-dependent aspartate-directed protease-1 (caspase-1) (Broz & Dixit 2016) (Fig. 1). Structurally, NLRP3 contains three important domains: an N-terminal pyrin domain (PYD), a central nucleotide-binding domain (NBD), and a C-terminal leucine-rich repeat (LRR) domain (Broz & Dixit 2016). The adaptor protein ASC contains a PYD and a caspase recruitment domain (CARD), which facilitate interactions between NLRP3 and caspase-1 that carries a CARD (Broz & Dixit 2016). When NLRP3 responds to PAMPs or DAMPs, it interacts with ASC and caspase-1.
NLRP3 inflammasome activation. NLRP3 inflammasome activation comprises a two-step process. During the priming step, a Toll-like receptor mediates the downstream NF-kB translocation to the nucleus and produces NLRP3 and pro-IL-1B. During the following activation step, NLRP3 oligomerises and recruits ASC. Subsequently, pro-IL-1B, pro-IL-18, and gasdermin D (GSDMD) are cleaved by active caspase-1 and released. The released GSDMD triggers pyroptosis.
Citation: Journal of Endocrinology 257, 2; 10.1530/JOE-22-0184
NLRP3 inflammasome activation comprises a two-step pathway in rodent macrophages, but not in human macrophages or dendritic cells (Netea et al. 2009, Gaidt et al. 2016) or in rodent dendritic cells (He et al. 2013). In response to the first signal (step 1), inflammasome components (e.g. NLRP3 and pro-IL-1B) are primed through activation of the NF-kB transcription factor, a downstream signal of the toll-like receptor (TLR). In response to the second signal (step 2), NLRP3 oligomerises through the NBD and recruits ASC through the PYD to form an ASC speck. Oligomerised ASC then recruits caspase-1 through the CARD to activate caspase-1 via proximity-induced self-cleavage. Activated caspase-1 cleaves pro-IL-1B and pro-IL-18, leading to the maturation and release of IL-1B and IL-18 (Swanson et al. 2019). In addition, activated caspase-1 also cleaves gasdermin D (GSDMD), which inserts into the membrane to form pores and induce pyroptosis (Swanson et al. 2019). Both caspase-1-mediated pyroptosis and the secretion of IL-1B are critical for reducing microbial infection and improving tissue repair (Broz & Dixit 2016).
The role of the NLRP3 inflammasome in metabolic diseases
Elevated IL-1B and IL-18 levels are associated with obesity, insulin resistance, dyslipidaemia, and metabolic syndrome (Hung et al. 2005). When PAMPs or DAMPs trigger the innate immune system, the NLRP3 inflammasome is assembled to promote the maturation and secretion of IL-1B and IL-18 and initiate the inflammatory response. However, excessive inflammasome activation leads to tissue damage and promotes disease progression (Carlsson et al. 2010). Several metabolic diseases with dysregulated inflammatory responses are induced by aberrant inflammasome activation and excessive IL-1B production (Fig. 2). The mechanisms by which NRLP3 inflammasome is involved in metabolic diseases are addressed in each metabolic DAMP.
NLRP3 inflammasome-related metabolic diseases. Serial DAMPs activate the NLRP3 inflammasome and contribute to various diseases. Because obesity is a common precursor for NLRP3-mediated metabolic diseases, it seems to prime the NLRP3 inflammasome. In the progression of atherosclerosis, cholesterol crystals or serum amyloid A (SAA) can trigger NLRP3 inflammasome activation. Gout, an inflammatory disease that can be caused by uric acid crystal deposition, is also a potent NLRP3 activator. Amylin (IAPP) deposition and high glucose levels in diabetes are related to NLRP3 inflammasome activation. The obesity-associated factors, palmitate and ceramide, are activators of NLRP3. Pathogenesis of NASH also involves palmitate-induced release of danger signals and the activation of the NLRP3 inflammasome.
Citation: Journal of Endocrinology 257, 2; 10.1530/JOE-22-0184
Several mechanisms underlie the activation of the NLRP3 inflammasome in response to various stimuli (Fig. 3). For example, the change in cytoplasmic potassium (K+), chloride (Cl−), or calcium (Ca2+) levels, the elevation of active cathepsin B in lysosomal disruption, and mitochondrial dysfunction and the release of reactive oxygen species (ROS) are all potent NLRP3 inflammasome activators (Swanson et al. 2019).
NLRP3 inflammasome activators. P2X7 is stimulated by ATP and serum amyloid A, subsequently regulating downstream K+ efflux and resulting in NLRP3 inflammasome activation. Uric acid and cholesterol crystals destabilise the lysosome, leading to the release of cathepsin B and the activation of the NLRP3 inflammasome. ROS stress derived from dysfunctional mitochondria and cytosol, which can be stimulated by glucose and amylin, is also a potent activator of the NLRP3 inflammasome. Palmitate activates the NLRP3 inflammasome by regulating the AMPK–autophagy–ROS pathway. Ceramide initiates mitochondrial dysfunction and activates the NLRP3 inflammasome.
Citation: Journal of Endocrinology 257, 2; 10.1530/JOE-22-0184
The contribution of ROS in NLRP3 inflammasome activation
Although ROS production represents an evolutionarily conserved pathway in response to infection, it is also a specific metabolic product of redox reactions. Most of NLRP3 activators, including the two well-known inducers, adenosine triphosphate (ATP) and particulate, trigger ROS production, while antioxidants inhibit NLRP3 inflammasome activation, suggesting that ROS is involved in NLRP3 activation (Dostert et al. 2008). A redox-sensitive protein can partly explain the link between ROS and inflammasome activation. For example, the generated ROS are sensed by thioredoxin and thioredoxin-interacting protein (TXNIP), which form a complex under the reducing condition. ROS induced by NLRP3 stimuli oxidises thioredoxin, leading to its dissociation from TXNIP. The released TXNIP then binds to NLRP3, triggering the activation of the NLRP3 inflammasome in THP-1 human macrophages. TXNIP deficiency impairs NLRP3-induced caspase-1 activation and IL-1B secretion in macrophages by several agonists, including R837, monosodium urate (MSU), alum or silica, and ATP (Zhou et al. 2010). While numerous NLRP3 activators induce inflammasome activation via the ROS-TXNIP pathway, this mechanism cannot count for all scenarios in ROS-mediated NLRP3-inflammasome activation. Moreover, the role of ROS in NLRP3 inflammasome activation has been challenged. While many cellular stresses produce ROS, not all activate the NLRP3 inflammasome. In addition, ROS inhibitors at high dosages have been shown to be involved in the signal-1, but not signal-2 pathway in mouse macrophages (Bauernfeind et al. 2011), suggesting that the conclusion of ROS resulting from chemical inhibitors should be made with caution. Thus, the detailed mechanism by which ROS is involved in NLRP3 inflammasome activation should be further verified.
ROS are composed of various species, including hydroxyl radical (HO•), hydroxide ion (HO−), triplet oxygen (O22•), superoxide anion (O2•−), peroxide ion (O22−), hydrogen peroxide (H2O2), peroxynitrite (ONOO−), and nitric oxide (NO•). There exists evidence of the involvement of specific species of ROS on NLRP3 inflammasome activation. For example, direct H2O2 treatment is sufficient to trigger NLRP3 inflammasome activation and IL-1B secretion in THP-1 cells (Zhou et al. 2010). Treatment of hydrogen, an antioxidant that can selectively scavenge HO•, suppresses IL-1B production and caspase-1 activity in LPS-stimulated RAW264.7 cells (Ren et al. 2016). A peroxynitrite ONOO− scavenger 5,10,15,20-Tetrakis(4-sulfonatophenyl) porphyrinato iron (III) chloride (FeTPPS) attenuates nigericin-induced caspase-1 activation and IL-1B secretion in human monocytes (Hewinson et al. 2008). Scavenging of O2•− by TEMPOL (4-hydroxy-2,2,6,6-tetramethylpo-peridine 1-oxyl) inhibits homocysteine-induced NLRP3 inflammasome activation and IL-1B production in mouse podocytes (Abais et al. 2014). Therefore, these results suggest that various oxidant species can activate the NLRP3 inflammasome. More studies using species-specific scavenger or gene knockout mice would be required to dissect various ROS species' contributions to NLRP3 inflammasome activation.
The source of ROS generated during NLRP3 inflammasome activation remains debated. ROS can be derived from mitochondria, NADPH oxidases (NOX), or xanthine oxidase. Cytosolic ROS are previously thought to be one of the common triggers in NLRP3 inflammasome activation (Dostert et al. 2008). However, attenuation of cytosolic ROS generation by loss of NADPH oxidase activity retains normal activation of NLRP3 inflammasome in mouse peritoneal macrophages and bone marrow-derived macrophages (BMDMs) (Hornung et al. 2008, Bulua et al. 2011). These studies argue the role of cytosolic ROS in NLRP3 inflammasome activation. Another source of ROS is derived from xanthine oxidase and has been linked to the activation of NLRP3 inflammasome. For example, a xanthine oxidase inhibitor allopurinol abrogates TLR7/8 activation-induced ROS production, caspase-1 and IL-1B processing in THP-1 cells and in mice (Nicholas et al. 2011). Treatment of vascular smooth muscle cells and THP-1 cells with xanthine oxidase activates NLRP3 and results in form cell formation in concert with ROS generation (Dai et al. 2017).
Mitochondria are another significant source of cellular ROS via the mitochondrial respiratory chain. Lately, mitochondrial ROS (mtROS), generated through dysfunctional mitochondria during cellular stress, are thought to be the predominant ROS in the activation of the NLRP3 inflammasome (Xue et al. 2017). The study in THP-1 cells using mitochondrial complex inhibitors for mtROS production was initially proposed to be the link between mitochondrial dysfunction and NLRP3 inflammasome activation (Zhou et al. 2011). Interestingly, mtROS are critical for NLRP3 inflammasome activation in one study using BMDMs (Gross et al. 2016) but appear dispensable in another study using the same cells (Munoz-Planillo et al. 2013). The involvement of mitochondrial perturbation and associated mtROS production remains debated for NLRP3 inflammasome activation.
In addition to mtROS, other materials released from dysfunctional mitochondria are potent triggers for NLRP3 inflammasome activation. For example, mitochondrial DNA released into the cytosol has been shown to interact and activate NLRP3 inflammasome in BMDMs (Shimada et al. 2012). Cardiolipin, a specific lipid within the mitochondrial inner membrane, is flipped to the outer membrane and interacts with the LRR of NLRP3 in mouse macrophage J774A.1 cells (Iyer et al. 2013). The mitochondrial antiviral signalling protein (MAVS), an outer mitochondrial membrane-associated protein, mediates NLRP3 mitochondrial recruitment through the direct NLRP3–MAVS interaction. MAVS is required not only for NLRP3 localisation to the mitochondria but also for NLRP3 oligomerisation in response to mtROS in BMDMs (Subramanian et al. 2013, Buskiewicz et al. 2016). Thus, perturbation of mitochondria is pivotal for NLRP3 inflammasome activation for more than the generation of mtROS.
Metabolic DAMPs in NLRP3 inflammasome activation
Several metabolic DAMPs directly activate the NLRP3 inflammasome. First, ATP and serum amyloid A (SAA) can stimulate P2X7 channels and promote K+ efflux to induce activation of NLRP3 inflammasome (Niemi et al. 2011, Gustin et al. 2015). Second, crystals and particulate structures (e.g. uric acid and cholesterol) lead to lysosomal dysfunction, destabilising lysosomes and releasing the protease cathepsin B. NLRP3 then senses the leakage of cathepsin B to induce inflammasome activation (Hornung et al. 2008). Third, mitochondrial dysfunction and mtROS release into the cytosol are critical events in NLRP3 activation. Obesity-associated metabolic DAMPs (e.g. palmitate and ceramide) damage mitochondria and increase mtROS production, which activates the NLRP3 inflammasome (Sharma & Kanneganti 2021). Additionally, other metabolic DAMPs (e.g. amylin and glucose) stimulate NLRP3 to assemble the inflammasome complex in multiple pathways involving the production of ROS (Masters et al. 2010, Zhou et al. 2010). In the following section, we discuss metabolic DAMPs that can potentially serve as great sources and potent inducers of activation of the NLRP3 inflammasome.
Adenosine triphosphate
ATP serves as both an energy and a signalling molecule. Extracellular ATP (at concentrations of ~0.05–1 mM) activates the purinergic receptor P2X7, resulting in plasma membrane depolarisation, rapid influx of Na+ and Ca2+, and efflux of K+ and other cations (Surprenant et al. 1996). K+ efflux is a key step in NLRP3 activation. Thus, blockade with high extracellular K+ or P2X7 inhibition suppresses ATP-induced IL-1B and caspase-1 release in mouse macrophage J774A.1 cells. These results suggest a mechanism whereby P2X7 activation triggered by ATP regulates K+ efflux and subsequent activation of NLRP3 inflammasome (Yaron et al. 2015). A decrease in intracellular K+ concentration facilitates a structural change in NLRP3 during its activation in BMDMs. A unique linker sequence and a short FISNA (fish-specific NACHT associated) domain located between PYD and NBD domains of NLRP3 are important for its sensing to decrease intracellular K+ (Tapia-Abellan et al. 2021), and this regulation is mediated through the essential mediator NIMA-related kinase-7 (NEK7) (He et al. 2016).
Serum amyloid A
SAA is an acute-phase serum protein produced by hepatocytes and adipose tissues. SAA induces the secretion of IL-1B from macrophages, dendritic cells, and neutrophils by activating the NLRP3 inflammasome and caspase-1 (Niemi et al. 2011, Shridas et al. 2018). However, different mechanisms are involved in the SAA-induced activation of the NLRP3 inflammasome. For example, oxidised ATP and KN-62, both P2X7 inhibitors, significantly reduced SAA-induced IL-1B release from human macrophages, suggesting that P2X7 signalling is involved in SAA-mediated inflammasome activation (Niemi et al. 2011). Moreover, SAA induces the secretion of caspase-1, ASC, and the active form of cathepsin B, and these processes have been detected after stimulation with P2X7 (Niemi et al. 2011).
Although SAA-induced activation of NLRP3 inflammasome is mediated through cathepsin B, it does not necessarily involve phagocytosis of SAA and lysosomal destabilisation (Niemi et al. 2011). Thus, SAA-induced NLRP3 inflammasome activation occurs via a unique P2X7–cathepsin B-dependent mechanism. However, SAA-induced inflammasome activation has also been reported to occur through a P2X7-independent mechanism. In mouse J774.2 macrophage-like cells, specific P2X7 receptor antagonists (AZ10606120 and A438079) failed to reduce SAA-induced IL-1B production. Despite different P2X7 dependencies, SAA mediates the activation of NLRP3 inflammasome via a mechanism involving cathepsin B activity in macrophage-like cells (Shridas et al. 2018).
Serum SAA level is elevated in many chronic inflammatory diseases, including obesity, type 2 diabetes, rheumatic diseases, and atherosclerosis, where IL-1B is predominant (Shridas et al. 2018). Overexpression of SAA increases atherosclerosis through increased inflammatory cell infiltration in ApoE−/− mice (Dong et al. 2011). In addition to activating the NLRP3 inflammasome, SAA alters vascular function, affects HDL function, and increases thrombosis in mice (Shridas et al. 2018). Although there is evidence that increased SAA levels are associated with cardiovascular diseases, it is not yet clear how SAA initiates and develops atherosclerosis through NLRP3 inflammasome activation.
Uric acid
Uric acid is a by-product of purine metabolism. MSU, the crystal form of uric acid, requires phagocytosis for uptake. Crystalline and particulate activators of the inflammasome cause destabilisation of the lysosomal compartment and release of cathepsin B. NLRP3 then senses the leakage of cathepsin B to trigger activation of the inflammasome (Jin & Flavell 2010). This causes the activation of caspase-1 and the release of mature IL-1B in human peripheral blood mononuclear cells (Hornung et al. 2008). Cathepsin B deficiency inhibits ASC oligomerisation and the formation of the NLRP3 inflammasome complex induced by MSU in BMDMs. These findings illustrate the importance of the lysosome-cathepsin B pathway in NLRP3-mediated ASC oligomerisation, caspase-1 cleavage, and IL-1B maturation (Chevriaux et al. 2020). Moreover, the co-localisation of NLRP3 and cathepsin B at the endoplasmic reticulum has been demonstrated in BMDMs treated with MSU (Chevriaux et al. 2020), suggesting that cathepsin B needs to be localised outside of the lysosome to contact NLRP3 at its inactive location in the endoplasmic reticulum. Moreover, the lysosome–cathepsin B pathway has been shown to activate the ROS pathway (Chevriaux et al. 2020). Hence, MSU-induced NLRP3 inflammasome complex formation involves the lysosome/cathepsin B pathway, with some contribution by ROS.
IL-1B, a key regulatory pro-inflammatory cytokine in gout, promotes neutrophil influx into the synovium and joint fluid, the pathological hallmark of gout attack. In the pathogenesis of gout, MSU uptake by macrophages activates the NLRP3 inflammasome, increasing IL-1B levels, recruiting neutrophils, and subsequently causing tissue damage in the joint (Martinon et al. 2006). NLRP3 inflammasome inhibitors and IL-1B inhibitors, such as anakinra (an IL-1R antagonist), have been tested in clinical trials to treat acute and chronic gout patients (Yang et al. 2022).
Cholesterol
Cholesterol, a type of lipid, is an essential structural component of cell membranes. Cholesterol crystals are solid, crystalline forms of cholesterol found in gallstones and atherosclerotic plaques. It has been reported that cholesterol crystals can induce activation of the NLRP3 inflammasome via signal-1 and signal-2 pathways. In the signal-1 pathway, treatment with cholesterol crystals exacerbates lipopolysaccharide (LPS)-induced expression of inflammasome-related genes in primary human macrophages (Rajamaki et al. 2010, Baldrighi et al. 2017). In the signal-2 pathway, cholesterol crystals destabilise lysosomes and cause leakage of cathepsin B into the cytoplasm, resulting in activation of the NLRP3 inflammasome in THP-1 cells (Rajamaki et al. 2010). The enrichment of cholesterol crystals in lysosomes can directly alter the content of the cholesterol membrane, leading to lysosomal instability in THP-1 cells (Thacker et al. 2016). Therefore, the formation of cholesterol crystals in LPS-primed murine macrophages induces lysosomal damage and subsequent NLRP3 inflammasome activation, resulting in the production of IL-1B and IL-18 (Duewell et al. 2010). Moreover, cholesterol crystals can enhance NLRP3 inflammasome activation by increasing the expression of CD36 in BMDMs. CD36 is responsible for the uptake of oxidised (ox)LDL into macrophages, leading to further augmentation of intracellular cholesterol crystallisation and activation of the NLRP3 inflammasome (Sheedy et al. 2013). These results highlight the dual role of cholesterol crystals in the priming of NLRP3 and activation of the NLRP3 inflammasome.
Cholesterol crystal deposition in the artery has been a hallmark of the early atherosclerotic lesion. Cholesterol crystals activate the NLRP3 inflammasome and consequent IL-1B production in minimally modified low-density lipoprotein (mmLDL)-primed murine macrophages (Duewell et al. 2010). Increased IL-1B levels promote neutrophil infiltration in atherosclerotic lesions and atherosclerosis progression (Duewell et al. 2010).
Palmitate
Obesity-associated danger signals, such as palmitate and ceramide, induce activation of the NLRP3 inflammasome in a ROS-dependent manner. Saturated fatty acid palmitate results in NLRP3 inflammasome activation and IL-1B release in a mtROS-dependent manner in BMDMs. The AMPK activator reduces palmitate-induced mtROS generation, suggesting that AMPK negatively controls mtROS levels induced by palmitate treatment. However, palmitate inactivates AMPK, leading to defective autophagy and increased mtROS, presumably due to a deficiency in the clearance of dysfunctional mitochondria. Thus, palmitate causes activation of the NLRP3 inflammasome and release of active IL-1B via an AMPK–autophagy–mtROS pathway (Wen et al. 2011).
In the development of insulin resistance induced by a high-fat diet, accumulation of saturated fatty acids, such as palmitate, induces NLRP3 inflammasome activation, causing maturation of caspase-1 and production of IL-1B and IL-18 in BMDMs (Wen et al. 2011). NLRP3 inflammasome activation in macrophages further impairs insulin signalling in target tissues, reducing insulin sensitivity and glucose tolerance. In non-alcoholic steatohepatitis (NASH), palmitate-induced apoptosis causes the release of danger signals from mouse hepatocytes, which in turn activate the NLRP3 inflammasome and increase IL-1B levels in Kupffer cells (Csak et al. 2011).
Ceramide
In lipid metabolism, palmitate enters the non-oxidative pathway and is converted into ceramide via irreversible condensation with l-serine. Ceramides and other sphingolipids are structural components of membranes and signalling molecules that regulate cell homeostasis (Gault et al. 2010). In BMDMs, ceramide induces mitochondrial oxidative stress to drive NLRP3 and caspase-1 activation (Camell et al. 2015). Aberrant ceramide accumulation is found in obese rodents and in insulin-resistance human subjects (Adams et al. 2004, Bijl et al. 2008). Thus, in the progression of obesity, lipotoxicity-associated ceramide activates the NLRP3 inflammasome to cleave caspase-1 in mouse macrophages and adipose tissues (Vandanmagsar et al. 2011). NLRP3 deletion in mice attenuates obesity-induced inflammation and enhances insulin signalling in adipose tissues and liver (Vandanmagsar et al. 2011).
Amylin/islet amyloid polypeptide
Amylin (also known as islet amyloid polypeptide (IAPP)), a hormone secreted by β-cells, forms amyloid deposits in the pancreas during the development of type 2 diabetes. Phagocytosis of amylin by BMDMs results in ROS generation, triggering NLRP3 inflammasome activation and mature IL-1B release, which requires priming with mmLDL (Masters et al. 2010). The IL-1B released by the infiltrated macrophages causes pancreatic β-cell death in vitro and in vivo (Dinarello et al. 2010). Along with the ROS-mediated mechanism, amylin has also been shown in BMDMs to prime the NLRP3 inflammasome for IL-1B production through MyD88 (Westwell-Roper et al. 2011). Additionally, amylin directly binds to the LRR domain of NLRP3 in β-cells to contribute to inflammation and β-cell death in pancreatic islets of patients with type 2 diabetes (Morikawa et al. 2018). Thus, amylin-mediated NLRP3 inflammasome activation and pancreatic β-cell death in type 2 diabetes involve ROS-sensitive and ROS-independent mechanisms. In the pathogenesis of type 2 diabetes, amylin activates the NLRP3 inflammasome and produces IL-1B in pancreatic dendritic cells and macrophages; increased IL-1B levels further promote β-cell death (Masters et al. 2010).
Glucose
Glucose is the most critical energy source in living cells. High glucose levels have been shown to induce ROS generation (Zhou et al. 2010), suggesting that hyperglycaemia causes activation of the NLRP3 inflammasome through oxidative stress. Moreover, the ROS inhibitor (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) attenuates the activation of the NLRP3 inflammasome and secretion of IL-1B induced by glucose (Zhou et al. 2010). After a glucose-induced increase in ROS levels, TXNIP is dissociated from oxidised thioredoxin and subsequently binds to NLRP3 (Zhou et al. 2010). Additionally, glucose-induced ROS production is sufficient to act as signal-2 to promote NLRP3 inflammasome activation for processing caspase-1 and IL-1B in mouse pancreatic islets (Feng et al. 2016).
In pancreatic islet failure during type 2 diabetes, glucose induces ROS production, which triggers TXNIP-thioredoxin dissociation and NLRP3 inflammasome activation in β-cells. Together with the previously addressed effect of amylin on NLRP3 inflammasome activation in BMDMs, which is independent of TXNIP (Masters et al. 2010), IL-1B secreted from both sources accelerates β-cell mass loss and promotes further immune cell infiltration, leading to pancreatic islet failure and progression to diabetes.
In conclusion, activation of the NLRP3 inflammasome and subsequent maturation and secretion of its downstream product (IL-1B) are involved in the interplay between macrophages and their local target cells, thereby participating in the pathogenesis of several metabolic diseases. Thus, identification of the unknown metabolic DAMPs and dissection of the novel mechanism should ultimately help design therapeutic targets for metabolic diseases associated with activating the NLRP3 inflammasome.
Endogenous ‘pedal and brake’ for NLRP3 inflammasome activation
Each of the three domains of NLRP3 (PYD, NBD, and LRR) has a unique feature in regulating inflammasome activation. For example, PYD forms self-association or homotypic interactions (PYD–PYD) with other members of this family (Abderrazak et al. 2015). NBD, associated with NLRP3 self-oligomerisation, is a domain involved with nucleotides, ATP binding, and hydrolysis (Lechtenberg et al. 2014). The LRR domain acts as a self-inhibitory domain that curves back to block NBD (Lechtenberg et al. 2014) and a ligand-detecting domain that breaks down the self-inhibitory interaction between NBD and LRR to promote inflammasome activation (Latz 2010).
Because NLRP3 serves as a converging point in recognising many danger signals, numerous NLRP3 regulating proteins have been discovered over the last few years. For example, pyrin-only proteins interact with ASC to block inflammasome formation (Bedoya et al. 2007), whereas CARD-only proteins interact with caspase-1 to reduce caspase-1 activity during inflammasome activation (Latz et al. 2013). Therefore, protein–protein interactions are crucial and potential regulators of NLRP3 inflammasome activation. Here, we demonstrated that several proteins regulate NLRP3 inflammasome activation via domain–domain interactions, including some regarded as ‘a pedal to accelerate’ and some as ‘a brake to slow down’ inflammasome activation (Fig. 4).
NLRP3 binding partners and domain interaction. NLRP3 is composed of three domains, LRR, NBD, and PYD. NLRP3 inflammasome activation is mediated by various proteins with different domains. GBP5 activates the NLRP3 inflammasome by binding to PYD, MARK4 by binding to NBD and PYD, HSP90 to LRR, and TXNIP and NEK7 to LRR and NBD. GNB1 and SHP inhibit the NLRP3 inflammasome by binding to PYD, and PPARG by binding to LRR and NBD. The inhibitory domain of NLRP3 mediated by HSP70 remains unclear. Metabolic DAMPs and related metabolic diseases associated with NLRP3 binding partners are shown.
Citation: Journal of Endocrinology 257, 2; 10.1530/JOE-22-0184
Guanylate-binding protein 5
Guanylate-binding protein 5 (GBP5) belongs to the GTPase family induced by LPS and interferon-gamma and is a key contributor to protective immunity against microbial and viral pathogens. GBP5 is critical in NLRP3 inflammasome activation induced by ATP, MSU, and pathogenic bacteria, but not particulate (Shenoy et al. 2012). GBP5 promotes bacteria-induced activation of the NLRP3 inflammasome through binding to the PYD of NLRP3. GBP5 deficiency attenuated LPS-induced caspase-1 cleavage and release of IL-1B and IL-18 in BMDMs and impaired host defence (Shenoy et al. 2012). However, another study shows contradictory results in unprimed BMDMs (Man et al. 2015). Although GBP5 is an activator for the NLRP3-ASC oligomerisation complex, further clarification is required. One recent study showed a significantly increased expression of NEK7 and GBP5 in a diabetic mouse heart, suggesting the involvement of the NLRP3-NEK7-GBP5 pathway in the diabetic heart. Their study suggests that inflammation-induced cardiac cell pyroptosis mediated by GBP5 is the key player in the development and progression of diabetic cardiomyopathy (Elmadbouh & Singla 2021).
Microtubule affinity-regulating kinase 4
Microtubule affinity-regulating kinase 4 (MARK4) belongs to the serine/threonine kinase family that phosphorylates microtubule-associated proteins to bring about their microtubule detachment. Interestingly, MARK4 interacts with the PYD and NBD domains of NLRP3 to induce activation of NLRP3 inflammasome and release of IL-1B. Mark4−/− BMDMs reduced IL-1B production, specifically after activation by NLRP3 stimuli. Moreover, MARK4-deficient cells exhibited significantly reduced NLRP3–ASC association, suggesting that MARK4 is involved in NLRP3 complex formation. Furthermore, the MARK4 catalytic kinase and NLRP3 PYD–NBD domains are essential for this interaction. IL-1B production and neutrophil accumulation in the peritoneal lavage were markedly reduced in Mark4−/− mice challenged with MSU. Overall, MARK4 is required for NLRP3-mediated IL-1B production and inflammasome activation. A recent study showed that MARK4-dependent NLRP3 inflammasome activation in haematopoietic cells regulates atherosclerosis development (Clement et al. 2019). Moreover, circulating IL-1B, IL-18, NLRP3 inflammasome, and MARK4 expression are increased in diabetic patients and rats. High glucose mediated NLRP3 inflammasome activation via upregulation of MARK4 in human umbilical vein endothelial cells (Wang et al. 2020).
Heat shock protein 90
Heat shock protein 90 (HSP90), a molecular chaperone that facilitates protein folding, is required to protect NLRP3 from proteasome and autophagic degradations (Mayor et al. 2007, Piippo et al. 2018). HSP90 forms a complex with NLRP3 and retains it in a competent form to receive the activation signal. The interaction between the LRR domain of NLRP3 and HSP90 requires another protein suppressor of the G2 allele of SKP1 (SGT1) in THP-1 cells (Mayor et al. 2007). Treatment with the HSP90 inhibitor geldanamycin attenuated caspase-1 activity and IL-1B release in a human retinal pigment epithelial cell line exposed to MG-132 + BafA, suggesting that HSP90 inhibition attenuates inflammasome activation (Piippo et al. 2018). Hence, a mechanism involving SGT1, HSP90, and NLRP3 regulates innate immune responses.
Thioredoxin-interacting protein
TXNIP is a metabolic protein involved in redox regulation. TXNIP acts as a redox sensor by binding to thioredoxin under reducing conditions. ROS dissociates the complex and releases TXNIP to bind to the NBD and LRR of NLRP3 to promote activation of the NLRP3 inflammasome. TXNIP ablation reduces the secretion of active caspase-1 and IL-1B from the LPS-primed BMDM cells stimulated with various NLRP3 inflammasome activators (e.g. MSU, alum, silica, and ATP) (Zhou et al. 2010). However, another study shows a dispensable role of TXNIP in NLRP3 inflammasome activation induced by ATP, MSU, and amylin in BMDMs (Masters et al. 2010). Txnip−/− mice showed attenuated responses to MSU-induced neutrophil influx and IL-1B production (Zhou et al. 2010). Moreover, TXNIP deficiency protects the mice from diet-induced insulin resistance and type 2 diabetes (Alhawiti et al. 2017). Thus, TXNIP is a critical promoter of ROS-mediated activation of NLRP3 inflammasome and plays an essential role in regulating insulin resistance and pancreatic islet failure.
NIMA-related kinase-7
NIMA-related kinase-7 (NEK7) is a serine/threonine kinase that controls the cell cycle. Three groups independently identified NEK7 as a critical regulator for NLRP3 inflammasome activation (He et al. 2016, Schmid-Burgk et al. 2016, Shi et al. 2016). NEK7 is a core component specific to NLRP3 but not NLRC4 and AIM2 inflammasomes. Activation of the NLRP3 inflammasome in BMDMs requires binding the catalytic domain of NEK7 to the NBD and LRR domain of NLRP3, which is independent of NEK7 kinase activity (He et al. 2016). This binding is necessary for NLRP3–ASC complex formation, ASC oligomerisation, and caspase-1 cleavage in BMDMs (Shi et al. 2016). NEK7 is required for NLRP3 inflammasome activation that is induced by ATP, nigericin, MSU, and particulate in BMDMs and mouse peritoneal macrophages (He et al. 2016, Shi et al. 2016). Moreover, NEK7 acts as a downstream target of K+ efflux in regulating NLRP3 activation in BMDMs (He et al. 2016). Thus, K+ efflux promotes the interaction between NLRP3 and NEK7, essential for forming ASC speck and cleavage of caspase-1. The process examined in HEK293T cells is mediated via NEK7 interaction with the NBD and LRR domains of NLRP3 (He et al. 2016). Thus, NEK7 is essential for assembling and activating the NLRP3 inflammasome, particularly under K+ efflux conditions. In addition to the involvement of the NLRP3-NEK7 pathway in the diabetic mouse heart (Elmadbouh & Singla 2021), one recent study showed that protein levels of NEK7 and the NLRP3 inflammasome components, including NLRP3, ASC, and caspase-1, are significantly increased in the vasculature of patients with diabetic foot. Increased serum levels of IL-1B and IL-18, an indication of chronic inflammatory status, accompany this. These results suggest that NEK7 might mediate NLRP3 inflammasome activation in the pathogenesis of diabetic lower extremity arterial disease (Cai et al. 2020).
G protein subunit B1
G protein subunit B1 (GNB1) is a component of heterotrimeric G proteins, with mutations in GNB1 causing severe neurodevelopmental disabilities, hypotonia, and seizures (Petrovski et al. 2016). Although G protein-coupled receptors are associated with NLRP3 inflammasome activation (Rossol et al. 2012), whether they act through GNB1 to regulate the NLRP3 inflammasome remains to be clarified. GNB1 negatively regulates NLRP3 inflammasome activation by interacting with the PYD of NLRP3 and suppressing ASC oligomerisation. GNB1 knockdown in BMDMs did not affect the expression of NLRP3 and pro-IL-1B induced following LPS treatment but significantly enhanced caspase-1 activation and IL-1B release following ATP treatment. These results suggest that GNB1 is a negative regulator of NLRP3 inflammasome activation (Murakami et al. 2019).
Small heterodimer partner
Small heterodimer partner (SHP), an orphan nuclear receptor, regulates glucose and cholesterol metabolism. SHP has been shown to influence its target genes directly or indirectly (Zhang et al. 2011). Interestingly, SHP interacted with the PYD of NLRP3 to inhibit the NLRP3–ASC interaction, leading to decreased IL-1B and IL-18 secretion in BMDMs. SHP is involved in protection mechanisms against inflammation-related disease progression in several mouse models, including MSU-mediated peritonitis and acute renal tubular injury. SHP acts as a negative regulator for NLRP3 inflammasome activation (Yang et al. 2015).
Peroxisome proliferator-activated receptor gamma
Peroxisome proliferator-activated receptor gamma (PPARG), a ligand-activated nuclear receptor, plays a major role in the transcriptional regulation of energy metabolism by promoting adipocyte differentiation and insulin-sensitising potential. PPARG is known for its anti-inflammatory potential, mediated through NF-kB transrepression and the subsequent inhibitory effect on the expression of inflammatory cytokines. We have recently shown an additional anti-inflammatory role of PPARG in suppressing NLRP3 inflammasome activation, which is mediated through binding to NLRP3. PPARG inhibits NLRP3 inflammasome assembly by damping interactions between NLRP3–ASC and NLRP3–NLRP3 and NLRP3-dependent ASC oligomerisation. The interaction between the NBD and LRR domains of NLRP3 and the DNA-binding domain of PPARG mediates this inhibitory effect. Our study further found that PPARγ is required to limit NLRP3 inflammasome activation induced by metabolic DAMP, such as palmitate, in mouse macrophages. There exists a negative correlation between PPARγ and mature caspase-1 in circulating mononuclear cells of obese patients. Thus, PPARγ agonism may be a therapeutic option for targeting-NLRP3-related metabolic diseases (Yang et al. 2021).
Heat shock protein 70
Heat shock protein 70 (HSP70), another molecular chaperone, protects cells from the adverse effects of physiological stresses. Extracellular HSP70 functions as a DAMP to stimulate immune and inflammatory responses through TLRs, TLR2 and TLR4, resulting in sterile inflammation and amplification of current inflammation (Hulina et al. 2018). In contrast, intracellular HSP70 has been reported to bind to NLRP3 and downregulate NLRP3 inflammasome activation. However, the domains mediating the interaction between NLRP3 and HSP70 remain to be identified. Moreover, LPS is sufficient to induce ASC/NLRP3 speck formation in Hsp70−/− BMDMs but not in wild-type control cells (Martine et al. 2019).
Therapeutic targeting NLRP3 for metabolic diseases
Metabolic diseases are increasingly recognised as having an inflammatory component that contributes significantly to the disease progression. This is particularly important when aberrant NLRP3 inflammasome activation is predominantly involved in the pathogenesis of metabolic diseases. Several available strategies targeting NLRP3 inflammasome product, IL-1B, have been applied in treating metabolic diseases. For example, the IL-1 receptor antagonist anakinra, IL-1B neutralising antibody canakinumab, and the decoy IL-1 receptor rilonacept have beneficial effects on gout and type 2 diabetes (Larsen et al. 2007, Cavelti-Weder et al. 2011). It is promising to see the effects of such treatments on other inflammasome-mediated metabolic diseases, such as atherosclerosis, insulin resistance, and NASH. Thus, the clinical indications of IL-1 blockade on metabolic diseases are continuously expanding. It is worth mentioning that the involvement of inflammation likely varies between metabolic diseases. Certain metabolic diseases with a more prominent role of NLRP3-mediated IL-1B may benefit more from NLRP3 targeting therapy. Thus, targeting NLRP3-mediated IL-1B may only be effective in some metabolic diseases involving NLRP3 predominantly.
In addition to blocking the outcomes of inflammasome activation, therapies directly targeting NLRP3 or inflammasome components are of interest. Several lines of small molecules directly targeting NLRP3 have been discovered. For example, the diarylsulfonylurea compound MCC950 has therapeutic efficacy against several preclinical immunopathological models, including atherosclerosis (van der Heijden et al. 2017), type 2 diabetes (Zhai et al. 2018), and NASH (Mridha et al. 2017). In addition, CY-09, an analogue of C172 used for cystic fibrosis (Jiang et al. 2017), tranilast, an analogue of a tryptophan metabolite, used for allergy, asthma, and hypertrophic scars (Darakhshan & Pour 2015), and oridonin, the main ingredient of the herbal medicine used for inflammatory diseases (Ma et al. 2011), exhibit therapeutic potential in mouse models of type 2 diabetes. Since these inhibitors are initially recognised for treating various inflammatory diseases, their applications in metabolic diseases require more exploration.
Glyburide, the first compound identified to inhibit NLRP3 inflammasome, is a second-line antidiabetic medication that stimulates insulin secretion in pancreatic β-cells (Lamkanfi et al. 2009). Although the effect of glyburide on the inhibition of NLRP3 inflammasome activation in vitro is potent, its effect in animals requires a high dosage (Mangan et al. 2018). While its mechanism of action remains unknown, it is likely to function downstream of the P2X7 receptor and upstream of NLRP3. Moreover, several P2X7 inhibitors and caspase-1 inhibiting pro-drugs have been discovered (Swanson et al. 2019). However, their effects on metabolic diseases await future studies.
Anti-inflammatory effect of metabolic drugs
In addition to targeting inflammation, NLRP3, and inflammasome components, several metabolic drugs show promising effects on attenuating NLRP3 inflammasome activation. Interestingly, the anti-inflammatory effect is frequently seen when treating these metabolic drugs, suggesting a close link between metabolic danger signals and inflammatory conditions. Thus, the anti-inflammatory effect of these metabolic drugs could result from resolving the accumulated metabolic DAMPs, such as glucose, palmitate, and cholesterol, by treatment.
Metformin, a first-line antidiabetic medication, exerts anti-inflammatory effects (Bulcao et al. 2007). For example, metformin treatment attenuated the upregulation of NLRP3 inflammasome activation in circulating macrophages of type 2 diabetic patients (Lee et al. 2013). Metformin also reverses the decreased expression of thioredoxin in the aorta of ApoE−/− mice (Tang et al. 2019). Thus, the beneficial effects of metformin on the amelioration of both inflammation and metabolic disorder could involve an NLRP3-based mechanism.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce circulating glucose levels in type 2 diabetic patients by increasing glucose excretion via inhibiting renal SGLT2 reabsorption. Treatment with SGLT2i dapagliflozin reduced IL-1B secretion in the macrophages of type 2 diabetic patients and NLRP3 inflammasome activation in activated B cells (Kim et al. 2020). Another SGLT2i empagliflozin decreased NLRP3 inflammasome activation and downstream inflammatory responses in the diabetic mouse kidney (Benetti et al. 2016). Thus, SGLT2i appears to exert anti-inflammatory effects by inhibiting NLRP3 inflammasome activation.
Dipeptidyl peptidase-4 inhibitors (DPP4i) exhibit glucose-lowering effects by inhibiting glucagon release and increasing insulin secretion. Treatment with DPP4i saxagliptin attenuated renal NLRP3 activity and injury in diabetic mice (Birnbaum et al. 2016). Resveratrol, a plant polyphenol found in red grapes, is known to have anti-inflammatory effects and exhibits glucose-lowering effects in clinal trials (Berman et al. 2017, Ozturk et al. 2017). Treatment with resveratrol attenuated TXNIP-mediated NLRP3 inflammasome activation in diabetic rats subjected to acute kidney injury and in human kidney proximal tubular HK-2 cells in high glucose condition (30 mM) subjected to hypoxia/reoxygenation (Xiao et al. 2016). Therefore, DPP4i and resveratrol both benefit by involving an NLRP3-related mechanism.
PPARγ agonists, an insulin sensitiser mentioned in the previous section, are well known for its anti-inflammatory effect. The anti-inflammatory role of PPARγ is initially thought to mediate through the transrepression of NF-κB and subsequent inhibition of cytokine transcription. Our group discovered an additional anti-inflammatory role for PPARγ that specifically targets NLRP3 inflammasome activation (Yang et al. 2021). In addition to the reduction of metabolic DAMPs (glucose and lipid), we also revealed a protein (NLRP3)-protein (PPARγ) interaction via the target protein of these metabolic drugs (Yang et al. 2021). Thus, the effects of metabolic drugs on the cure of metabolic diseases associated with the reduction in inflammatory status likely involve more than one mechanism. This highlights the crosstalk between metabolism and inflammation. Thus, inhibition of NLRP3 inflammasome activation can be achieved by improving metabolic pathways via various metabolic drugs.
Main gaps and recent novel development
In the past few years, inhibitors targeting IL-1B are increasing rapidly. Several of them are currently used in the clinical treatment of multiple inflammatory diseases. Several similar agents, such as neutralizing and blocking antibodies, are currently under development. However, several points should be noted. As IL-1B is not the only product of inflammasome activation, the involvement of other secretory mediators, such as IL-18 and HMGB1, in metabolic diseases cannot be neglected. Further, IL-1B can be produced from NLRP3 inflammasome-independent pathways or through the activation of other inflammasomes. Lastly, inhibitors targeting IL-1B can have detrimental effects on immune defence, and should be applied cautiously in the context of metabolic diseases.
Lately, a number of small molecules directly targeting NLRP3 or inflammasome components or its related signaling have been developed. As the inhibitory mechanisms or precise targets remain to be defined, most of these inhibitors raise concerns regarding off-target effects. Therefore, their potency for in vivo usage requires further evaluation. Although some of these inhibitors are being used in clinical practice, some have been suspended at phase II clinical trials because of hepatic toxicity (MacKenzie et al. 2010, Mangan et al. 2018). Therefore, the strategies for targeting NLRP3 inflammasomes as a therapeutic target for metabolic diseases need to be refined.
The application of metabolic drugs for inhibiting NLRP3 inflammasome activation is promising. Most of these metabolic drugs are being used in clinical practice or are being investigated in clinical trials with relatively high safety. In the past few years, the development of inhibitors targeting IL-1B and NLRP3 as therapeutics for multiple diseases has undergone major advances. The main limitations in developing NLRP3-related metabolic drugs are time-consumption and cost-effectiveness. Therefore, instead of repurposing of NLRP3 inhibitors for metabolic diseases, it may be more practical and feasible to repurpose metabolic drugs for targeting the NLRP3 inflammasome.
Conclusions and perspectives
Improving metabolic pathways has been associated with alleviating NLRP3 inflammasome activation, which might be related to a reduction in particular nutrients or metabolites acting as metabolic DAMPs to activate the inflammasome. This has received much attention in studying TLRs that sense various nutrients or metabolites in addition to the canonical activator PAMPs. Aberrant accumulation of these nutrients or metabolites in metabolic diseases indeed are endogenous DAMPs that are shown to be direct activators of the NLRP3 inflammasome, mainly involved in the initiation and progression of these diseases. Therefore, more nutrients or metabolites would be candidates for the accelerators of NLRP3 inflammasome activation.
Although not all of the abovementioned protein binding partners for NLRP3 have been directly linked to metabolic diseases, most are identified with inflammation. Because of their characteristics in physical contact with NLRP3, the involvement of these binding partners in metabolic diseases warrants future investigations. Based on the concept of the domain-domain interaction and the unique feature of the binding domain, other proteins with similar domain features may be candidates for searching for more NLRP3 binding partners. Moreover, small molecules targeting NLRP3 with known inhibitory domains on NLRP3 can be applied to stop the pedal action of binding partners listed in Fig. 4. Finally, as illustrated in Fig. 4, metabolic DAMPs may affect NLRP3 inflammasome activation via these binding partners. Attention can be focused on the crosstalk between metabolic DAMPs and protein binding partners.
In recent years, immuno-metabolism research has gained considerable attention due to the interplay between inflammatory responses and metabolism. Several metabolites, danger signals, enzymes, and nuclear receptors essential for energy sensing or metabolism have been implicated in the modulation of inflammatory responses. Therefore, it is necessary to dissect the link between metabolic factors and inflammation and to identify novel metabolic danger signals. This review highlights the induction by metabolic danger signals and regulation by protein binding partners of the NLRP3 inflammasome as potential therapeutic targets for metabolic diseases. Understanding how, what, and when metabolic factors modulate NLRP3 inflammasome activation could provide novel therapeutic approaches through the cautious manipulation of these metabolic factors.
Declaration of interest
The authors have declared that no competing interest exists.
Funding
This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST-107-2320-B-006-063-MY3, MOST-110-2320-B-006-017-MY3, and MOST-111-2320-B-006-022-MY3), National Health Research Institutes (NHRI-EX107-10511SI), National Cheng Kung University Hospital (NCKUH-10909039), and National Cheng Kung University and E-DA Hospital Research Project.
Author contribution statement
Sy-Ying Leu, Ching-Chun Yang, Li-Chun Ho, Ai-Ning Shao, and Chia-Yu Chang wrote the first draft; Yi-Ling Tsang drew the graphical illustration; Hui-Kuan Lin, Pei-Jane Tsai, and Junne-Ming Sung provided suggestions and discussion; Yau-Sheng Tsai made critical review of the manuscript; All authors read and approved the final manuscript.
Acknowledgements
The authors thank Editage for language editing.
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