Systemic lupus erythematosus (SLE) is a prototypic multisystemic autoimmune condition with unclear etiology, attributed to loss of immune tolerance towards autoantigens and production of antinuclear autoantibodies (Bentham et al., 2015). Nuclear autoantigens/antibody complexes are deposited in multiple organs, resulting in tissue damage and severe clinical manifestations, including malar rash, arthralgia, fever, renal failure, and cardiovascular diseases (Tanaka et al., 2018; Durcan et al., 2019). Lupus nephritis (LN) is a main clinical manifestation of SLE; it negatively affects the quality of life of SLE patients and their long-term prognosis (Davidson, 2016; Fanouriakis et al., 2020). Approximately 50% of SLE patients develop renal disease at some stage (Almaani et al., 2017). Hence, it is necessary to further elucidate LN-related pathogenic mechanisms to develop practical therapeutic approaches.

Inflammasome refers to multiprotein immune complexes assembled by pattern recognition receptors (PRRs) in the cytoplasm. Its activation mediates inflammatory responses to cellular damage and pathogenic microbial infections (Franchi et al., 2012; Strowig et al., 2012). As an important component of the innate immunity, inflammasomes operate as a central pathogenic mechanism in various diseases (Duncan and Canna, 2018; Yang et al., 2019; Spel and Martinon, 2020). Several studies have reported that the NACHT, leucine-rich repeat (LRR), and pyrin (PYD) domains-containing protein 3 (NLRP3) inflammasome is involved in the occurrence and development of LN (Zhao et al., 2015; Zhang et al., 2018a; Lin Q. et al., 2019). This study summarizes current knowledge on the role of the NLRP3 inflammasome in the pathogenesis of LN.

Recently, phytochemicals have attracted much attention due to their cost, efficacy, and safety (Zhang et al., 2018b). We also present a review of several phytochemicals that have been shown to interfere with NLRP3 inflammasome-related signaling pathways in the context of LN.

Inflammasomes mediate caspase-1 activation and induce the maturation and release of the proinflammatory cytokines IL-1 and IL-18, initiating a cascade of inflammatory responses. They also trigger caspase-1-dependent pyroptosis and induce cell death under pathologic inflammatory and stress conditions. Among different inflammasomes, the NLRP3 inflammasome has been the most extensively studied and elucidated (Hoffman et al., 2001). Different studies showed that activation of the NLRP3 inflammasome is closely related to multiple autoinflammatory diseases (Baroja-Mazo et al., 2014; Lu et al., 2017; Louvrier et al., 2020). Therefore, its role in LN pathogenesis has attracted more attention (Zhao et al., 2013a; Lech et al., 2015).

The NLRP3 inflammasome is a multiprotein oligomeric complex consisting of NLRP3, adapter apoptosis-associated speck-like (ASC) protein, and procaspase-1 (Martinon et al., 2009; Guo et al., 2015). NLRP3 inflammasome activation usually involves a priming step and an activation step (Latz et al., 2013). At priming, the engagement of PRRs, such as toll-like receptors (TLR) or cytokine receptors, activates the transcription factor NF-κB, which upregulates the expression of NLRP3 and pro-IL-1β and pro-IL-18 cytokine precursors (Mishra et al., 2013; Kelley et al., 2019).

At the activation stage, the NLRP3 inflammasome is activated through the recognition of various pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) molecules (Lamkanfi and Dixit, 2014; Swanson et al., 2019), including bacterial U1-snRNP, ATP, and dsDNA (Mariathasan et al., 2006; Shin et al., 2012; Muñoz-Planillo et al., 2013; Shin et al., 2013). These stimuli activate the NLRP3 inflammasome through several mechanisms that are not fully clarified. Current research suggests the potential involvement of K+ efflux, mitochondrial dysfunction, lysosomal rupture, or generation of reactive oxygen species (ROS) (Katsnelson et al., 2016; Yu and Lee, 2016; Han et al., 2018). In addition, NEK7 also interacts with NLRP3 and modulates the activation of NLRP3 inflammasomes (He et al., 2016; Chen et al., 2019).

Upon activation, the NLRP3 binds the stimulatory ligands and the NACHT domains promote self-mediated oligomerization of several NLRP3. NLRP3 combines with ASC through homotypic N-terminal PYD-PYD interactions. Assembled ASC recruits procaspase-1 through its C-terminal CARD-CARD interactions to form the NLRP3 inflammasome. Subsequently, the functional inflammasome initiates self-catalysis of procaspase-1 to caspase-1, followed by self-enzymatic hydrolysis of caspase-1, which generates the large p20 and small p10 subunits (Elliott and Sutterwala, 2015; Sharif et al., 2019). The p20 subunit converts pro-IL-1β and pro-IL-18 into IL-1β and IL-18, respectively, and promotes the secretion of these cytokines, which have a broad spectrum of inflammatory activities (Spalinger et al., 2017; Mende et al., 2018; Abbate et al., 2020). Simultaneously, activated caspase-1 cleaves gasdermin D (GSDMD) protein, leading to the formation of plasma membrane pores, triggering gasdermin D-mediated pyroptosis (Miao et al., 2010; He et al., 2015).

Studies have identified a noncanonical inflammasome representing another crucial mechanism of inflammasome activation (Kayagaki et al., 2011). Noncanonical inflammasomes are generally activated by Gram-negative bacteria-derived molecules, including intracellular lipopolysaccharides and toxins. These inflammasomes mediate the activation of intracellular receptors caspase-11 in mice and caspase-4 and caspase-5 in humans, which are oligomerized after binding LPS and activate pyroptosis, together with inflammatory responses (Shi et al., 2014; Kayagaki et al., 2015; Lagrange et al., 2018). In addition, there is evidence that caspase-8 participates in the activation of NLRP3 inflammasome in human monocytes through an alternative NLRP3 inflammasome pathway (Xiang et al., 2020). Under LPS stimulation, the NLRP3 inflammasome activation is triggered by the TLR4-TRIF-RIPK1-FADD-CASP8 cascade signaling pathway, which then activates caspase-1 and secretes IL-1β (Gaidt et al., 2016; Zito et al., 2020) (Figure 1).

LN results from the interactions between genetics, epigenetics, sex hormones, environment, and other factors (Cunningham et al., 2019; Rahbar Saadat et al., 2019; Wardowska et al., 2019). The core pathogenesis of LN is a loss of self-tolerance, leading to accumulation or deposition of autoantibodies and immune complexes in the kidney, activating the complement system and causing chronic inflammation (Wada et al., 2019). Renal lesions in LN patients are characterized by glomerulonephritis, vascular injury, and tubular atrophy, which eventually may progress to renal fibrosis or even renal failure (Leatherwood et al., 2019).

Recent findings showed that NLRP3 and associated inflammatory cytokines, including IL-1β and IL-18, are elevated in the blood and nephritis biopsies from LN patients (da Cruz et al., 2020; Huang et al., 2020). Moreover, to systematically explore the mechanisms of NLRP3 on LN, different mouse models have been analyzed. In several models, NLRP3 and related components are increased in LN mice compared with controls (Honarpisheh et al., 2016; Bonomini et al., 2019). In MRL/lpr mice, a spontaneous lupus model, the expression of NLRP3, ASC, and active caspase l-p20 subunit protein was upregulated in the kidney, compared with control mice. Furthermore, the IL-1β level was upregulated in renal homogenates. Blocking upstream P2X7 receptor inhibited NLRP3 inflammasome assembly and reduced proteinuria (Zhao et al., 2013b). Intraperitoneal injection of pristane stimulates the body to produce autoantibodies, which has become a classic model for SLE (Freitas et al., 2017). In Nlrp3 ^-R258W mutant mice, more severe renal pathological changes occurred when intraperitoneal injection with pristane and specific abrogation of Nlrp3 ^-R258W expression in myeloid cells conferred a therapeutic benefit to lupus Nlrp3 ^-R258W mutant (Lu et al., 2017).

Since the publication of histological classification criteria for LN, much attention has been focused on glomerulopathy in patients with LN and on the mechanisms of glomerular lesions. Subsequent revisions of previous knowledge have also been based on the pathological characteristics of glomerular damage (Azzouz et al., 2019; Dörner and Furie, 2019; Zhou et al., 2019). Endothelial cells, basement membrane, and podocytes form a glomerular filtration barrier, which plays a key role in maintaining the structure and function of the kidney (Nawata et al., 2018). Currently, research on NLRP3 in the context of LN mainly focuses on podocytes. The NLRP3 inflammasome activated in glomerular podocytes results in severe proteinuria in mouse lupus models and in patients with LN (Fu et al., 2017; Fu et al., 2019). Studies support a role for the NLRP3 inflammasome in promoting podocyte injury and proteinuria during LN. The level of activated caspase-1 in podocytes from LN NZM2328 mice with severe proteinuria is elevated, as well as in urine and tissue biopsies from patients with active LN. MCC950, an NLRP3 inhibitor, significantly inhibited caspase-1 in NZM2328 mouse podocytes by preventing NLRP3 inflammasome activation, ameliorated proteinuria, and reduced renal tissue damage. In vitro, sera from LN NZM2328 mice activated the NLRP3 inflammasome and increased the IL-1β level in podocytes by inducing ROS (Fu et al., 2017).

Evidence of RIP3 and necrotic pathway activity was found in podocytes from class IV LN patients and in the kidney of lupus-prone mice. GSK872, an inhibitor of RIP3, reduced anti-dsDNA antibody titer and the size and weight of the spleen, as well as RIP3 activation in podocytes. The upregulation of NLRP3, caspase-1 p20, and IL-1β levels induced by serum IgG from LN diseased NZM2328 mice could be inhibited by GSK872 (Guo et al., 2019).

As pointed out above, several studies have demonstrated that NLRP3 inflammasome components are involved in the pathogenesis of LN. Therefore, modulating NLRP3 inflammasome signals may represent a significant and promising target for LN management (Fu et al., 2019; Yang et al., 2020) (Table 1).

Common treatments for LN predominantly involve corticosteroids, antimalarial drugs, immunosuppressive agents, and biologics, which, although effective, are commonly associated with immunogenicity (Singh et al., 2016; Fava and Petri, 2019). Currently, available drugs do not meet the clinical demands for LN patients and are limited by suboptimal efficacy and severe side effects (Dall’Era et al., 2019; Murphy and Isenberg, 2019). There is increasing concern that drugs targeting the NLRP3 pathway may be appropriate for LN therapy (Lin T.-J. et al., 2019; Wu et al., 2020). Phytochemicals are secondary metabolites of plants with various bioactivity and are found in many herbs, fruits, and vegetables. Evidence suggests that phytochemicals have broad biological activities, including antioxidant, antiviral, and anti-inflammatory effects, and hold good prospects to treat autoimmune diseases and improve lipid metabolism among other diseases (Du et al., 2019; Guo et al., 2019; Hu et al., 2019a; McKee et al., 2020). To date, several phytochemicals have been shown to affect LN progression by inhibiting the NLRP3 inflammasome (Figure 2).

SLE is an autoimmune disease involving multiple system damage. LN is an important renal complication of SLE, its clinical manifestations are complex and diverse, and the course of the disease is protracted and difficult to heal. If not treated in time, LN seriously affects the quality of life and survival rate of the patients. So far, the etiology and pathogenesis of LN remain unclear. As indicated above, activation of the NLRP3 inflammasome can promote the occurrence and development of the pathological processes leading to LN by causing inflammatory responses. With extensive research on inflammasomes, our understanding of its impact and mechanism of action on LN has become deeper and broader. Treatments targeting the NLRP3 inflammasome have attracted increasing attention (Li et al., 2020). Current studies on NLRP3 inflammasome in LN mainly focus on the canonical NLRP3 inflammasome pathway and lacks the detection of noncanonical NLRP3 inflammasome-related indicators, such as caspase-11, caspase-4, and caspase-5. Compared with the inactive LN subgroup and healthy controls, the serum level of caspase-8 increased significantly in active LN (Petrackova et al., 2017). It is worth further verification whether caspase-8 is involved in the pathogenesis of LN through an alternative NLRP3 inflammasome pathway. The research on the noncanonical NLRP3 inflammasome and alternative NLRP3 inflammasome pathway is still in infancy, but whether they are involved in LN and what role they play in it deserve our attention and exploration.

At present, treatment options for LN are limited. The main treatments consist of corticosteroids, antimalarials, and immunosuppressants, but these induce adverse reactions, such as immunosuppression and increased infection susceptibility. Therefore, it is extremely valuable to develop more effective treatments involving drugs with safety. This article summarizes the research progress made in recent years related to the therapeutic effects of phytochemicals on LN, acting through the NLRP3 inflammasome (Figure 2). The research of phytochemicals on NLRP3 in LN is limited to NLRP3 itself and the inflammatory factors IL-1β and pro-IL-18. In the context of lupus, there may be more specific targets upstream or downstream of NRLP3. This could help identify the role of phytochemicals on these specific molecules in other types of pathology and be tested in the context of lupus. A better understanding of the activation mechanisms of the NLRP3 inflammasome in LN will provide new ideas and approaches for the treatment of LN by phytochemicals. In addition, the clinical treatment of LN requires long-term medication, and the safety evaluation of the therapeutic dose and duration of phytochemicals needs to be further verified. This is a promising area, but there are many gaps that we need to fill in. There are significant differences in the incidence and severity of LN between different regions and races globally, and women are higher than men (Almaani et al., 2017). As summarized in this article, most of the studies on NLRP3 inflammasome in LN reported so far have been conducted in mouse models, and studies on LN patients with different genetic backgrounds will further determine the role of NLRP3 inflammasome.