Helicobacter pylori (HP) is the only harmful pathogenic bacterium ever found that can survive in human gastric mucosa. HP is listed as a class I carcinogenic factor by the World Health Organization (WHO) and belongs to infectious diseases (28). It was found that the content of NLRP3 and GSDMD were significantly higher in the gastric tissues of HP-infected patients (29). Experiments showed that the early stages of HP infection activate the NLRP3 inflammasome by targeting hsa-miR-223-3p and IL-10 (30). HP also provides a second signal required for the activation of the NLRP3 inflammasome, including K⁺ efflux and ROS production, which leading to a rise in IL-1β secretion (31). During HP infection, considerable mature IL-1β could cause atrophic gastritis and even cancer (32). Koch KN et al. reported that excessive activation of NLRP3 inflammasome keeps HP away from the immune system, persistently colonizes, and survive in the gastric niche (33). HP infectious mice models with NLRP3 knocked-down or knocked-out were protected against gastritis (34). These results indicate that HP infection can promote NLRP3 inflammasome activation which is involved in the persistent infection of HP. In other words, the NLRP3 inflammasome and HP infection promote each other and form a vicious circle.

Gastric cancer (GC) is a malignant tumor that arises from the epithelial cells of gastric mucosa. It ranks fifth in terms of prevalence and third in terms of mortality around the world, with a poor prognosis (35). Persistent and chronic inflammation leads to the development of GC. NLRP3, as an essential inflammatory component, plays a crucial role in the progression of GC. The expression of NLRP3 in GC tissues exhibited a higher level than healthy tissues. Furthermore, redundant amount of ASC was found in most GC tissues in the Oncomine database and the The Cancer Genome Atlas (TCGA) database. It has been found that NLRP3 can enhance the uncontrolled proliferation of epithelial cells and the progression of GC. And when NLRP3 is inhibited, so does its carcinogenic influence in vitro and in vivo (36, 37). The NLRP3 inflammasome induces IL-1β production, and IL-1β can promote intestinal metaplasia, atypical hyperplasia, and proliferation of GC cells (38, 39). Therefore, NLRP3 by a combination of dependent and independent inflammasome pathways may stimulate GC development. Notably, the gene polymorphism of NLRP3 also impacts the pathogenesis of GC (40). These findings indicate that the NLRP3 inflammasome and its inflammatory products has a close relationship with GC development but more molecular pathways between the NLRP3 inflammasome and GC require further elucidation.

Chronic infection with viral hepatitis affects half a billion individuals worldwide (41). Chronic hepatitis B (CHB) is a inflammatory liver illness caused by persistent infection of hepatitis B virus (HBV), which is a non-cytopathic double-stranded, hepatotropic DNA virus. Expression levels of NLRP3, ASC, and IL-1β in liver tissues from CHB patients were positively correlated with HBV-DNA concentration (42). It has been confirmed that NLRP3, IL-18, IL-1β, and caspase-1 were highly expressed in liver tissues of patients with HBV-related acute-on-chronic liver failure (HBV-ACLF). Patients with HBV-ACLF are likely to have impaired immune systems due to chronic inflammation (43). Similarly, hepatitis B core antigen promoted the expression of NLRP3 inflammasome and IL-1β (44). These results might suggest that persistent infection with HBV makes the NLRP3 signaling pathway activated, which is involved in the inflammatory response and injury of liver tissues by mediating cytokines such as IL-1β, and IL-18. Whereas the specific mechanism of the NLRP3 inflammasome activation infected by HBV has not been well understood. Hepatitis virus C (HCV), as a hepatotropic and enveloped virus, carries a positive-sense single-stranded RNA genome, and chronically infects around 3% of people worldwide (45). Negash et al. showed that the serum levels of IL-1β were significantly increased in patients with chronic hepatitis C (CHC). Furthermore, they showed that HCV RNA triggers MyD88-mediated TLR7 signaling and the NLRP3 inflammasome pathway to induce IL-1β production (46). Once infected with HCV, ASC is recruited to NLRP3 and dissociates from Golgi-resident protein immunity-related GTPase M (IRGM), causing Golgi fragmentation. This process enhances the replication of HCV and promotes chronic inflammation of the liver (47). Ramachandran A et al. demonstrated that the NLRP3 inflammasome, assembled and activated in HCV-infected liver cells and regulated by post-translational modifications, was critical in the pathogenesis of CHC (48). A study found that inoculation with infectious Hepatitis E virus (HEV) particles robustly triggered NLRP3 inflammasome activation in primary macrophages and macrophage cell lines. Interestingly, inflammasome activation antagonizes interferon response to facilitate HEV replication in macrophages (49). Taken together, strategies to inhibit the NLRP3 inflammasome or its inflammatory cytokines provide therapeutic choice to alleviate the liver inflammation besides antiviral agents.

Non-alcoholic fatty liver disease (NAFLD) is a progressive hepatic disease with ectopic fat accumulation in the liver caused by harmful factors, other than alcohol. The prevalence of NAFLD varies between 19% and 33% in epidemiological studies and remains a challenging issue for human health (50). Multiple studies have demonstrated that the NLRP3 inflammasome is a pivotal contributor to the amplification of hepatic inflammation, immune cell activation, and hepatocyte damage (51). Caspase-1, the activated form after NLRP3 inflammasome activation, is present in the serum of patients with NAFLD, and its levels are closely correlated with disease severity (52). A high level of NLRP3 and caspase-1 is activated in macrophages in response to an excessive accumulation of lipids in dead hepatocytes (53). The NLRP3 inflammasome is associated with nonalcoholic steatohepatitis (NASH) which is a severe procedure in the advancement of NAFLD. NASH is distinguished from the NAFLD by the additional presence of features of hepatocellular injury with or without fibrosis (8). There is increasing evidence that NLRP3-mediated pyroptosis is key to the progression of simple steatosis to NASH (17, 54). Pyroptosis leads the NLRP3 inflammasome to the extracellular fluid. From there, the NLRP3 inflammasome is taken up by other cells, thus mediating inflammation and fibrosis (52). A study has confirmed that inhibition of pyroptosis can alleviate the inflammatory response of liver tissue by targeting the NLRP3 inflammasome (55). There is evidence that NLRP3 inflammasome plays a direct role during the development of NASH/NAFLD in mice models. It was found that mice with NLRP3 inflammasome loss of function are protected from diet-induced steatohepatitis (56). NLRP3 inflammasome gain of function leads to the early and severe onset of diet-induced steatohepatitis in mice (9). Inhibiting the NLRP3 inflammasome particularly alleviated inflammation, lipid accumulation, and fibrosis in NASH/NAFLD (5, 55, 57–59). Whereas there is also evidence that NLRP3 produces a hepatoprotective effect in NASH/NAFLD models. Jorge Henao-Mejia et al. observed that NLRP3-deficient aggravates NASH, which makes serum alanine transaminase(ALT), aspartate transaminase (AST), and NAFLD activity inflammation scores increase (60). The NAFLD mouse model lack of NLRP3 showed higher triglyceride content, histological score of liver injury and greater adipose tissue inflammation (61). Different metabolic processes, tissues, and mouse models could account for the above conflicting findings (61).

Alcoholic liver disease (ALD) is a kind of liver disease caused by long-term heavy drinking. The initial stage usually presents with alcoholic hepatitis and hepatic fibrosis, with the consequent risk of developing into cirrhosis or liver cancer. Severe alcoholism could induce extensive necrosis of liver cells and even liver failure. A preliminary study showed that the messenger RNA (mRNA) levels of the components of the NLRP3 inflammasome (IL-1β, IL-18, and caspase 1) tended to be greater in patients with severe liver damage (alcoholic hepatitis histological score≥5) than in patients with milder liver damage (62). Studies have demonstrated that long-term intake of alcohol facilitated liver damage and promoted the expression of IL-1β, caspase-1, ASC, and NLRP3 in wild-type (WT) mice (63). As for the mechanism of NLRP3 activation during ALD, it has been elucidated that the metabolic disorders of uric acid and ATP induced by alcohol could lead to mitochondrial damage, and the activation of NLRP3 inflammasome. Additionally, alcohol decreases miR-148a expression in hepatocytes through forkhead box protein O1 (FoxO1), facilitates TXNIP overexpression and activates the NLRP3 inflammasome, which induces hepatocyte pyroptosis and aggravates ALD (64). Recent studies have demonstrated that ethanol-induced NLRP3 activation was primarily caused by the downregulation of aryl hydrocarbon receptors and the activation of TXNIP in human macrophages, both of which were caused by oxidative stress (65). In summary, alcohol induces NLRP3 inflammasome activation through various pathways, and inhibition of NLRP3 inflammasome activation is capable of abating ALD (66, 67). On the contrary, it is also found that NLRP3 deficiency mice have more severe hepatic damage with higher levels of ALT and IL-18 levels (68). These contradictory outcomes could be explicated by various experimental conditions and approaches.

Drug-induced liver injury (DILI) refers to liver injury caused by various prescription or non-prescription drugs and their metabolites and excipients. Clinical manifestations of DILI are acute hepatitis, cholestasis, or jaundice. It develops independently of drug dose, route, or duration of administration (69). The pathogenesis of DILI is complex and different. If left untreated, liver failure may develop with high mortality. Rifampicin (RIF) and isoniazid (INH) are the classical anti-tuberculosis medicines (70, 71). However, INH and RIF can significantly change the structure of normal liver tissues and cause inflammation, leading liver damage or hepatotoxicity. Many researches had confirmed that the NLRP3 inflammasome was required for INH and RIF-induced liver injuries (5, 72). Moreover, the knock-down of NLRP3 with small interfering RNA (siRNA) dramatically changed the effects of INH and RIF on hepatocytes (73). It was found that the NLRP3 inflammasome was also the key to acetaminophen(APAP)-induced DILI (74). APAP-induced DILI is protected by aspirin and benzyl alcohol, which inhibit the activation of NLRP3 inflammasomes and neutrophil infiltration (75, 76). However, the role of the NLRP3 inflammasome in APAP-induced liver injury is disputed. Studies have described no protective effect if inflammasome components, such as NLRP3, caspase-1, ASC, are deficient in APAP-induced liver injury. The reason for these opposite results remains unclear (77).

Cholestasis, characterized by bile secretion disorder and excessive bile acid (BA) accumulation in the liver, is clinically associated with a variety of liver diseases, such as progressive familial intrahepatic cholestasis, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) etc. An injury to the liver caused by cholestatic disease results in the death of cells followed by inflammation and fibrosis. There is a correlation between NLRP3 activation and chronic cholestasis in humans and mice (78). Expression of NLRP3 was significantly elevated in bone marrow-derived monocytes/macrophages of bile duct ligation (BDL) mice (79). Twenty-eight days after BDL, bridging fibrosis was observed in WT mice instead of mice with NLRP3 knocked out. Lack of NLRP3 expression attenuated liver injury and fibrosis after acute and chronic BDL. The NLRP3 small molecule inhibitor MCC950 could reduce BDL-induced disease progression in WT mice (80) by reducing the production of the pro-inflammatory cytokines IL-1β and IL-18 and inhibiting neutrophil infiltration and hepatic cell death (72), emphasizing the importance of the NLRP3 inflammasome in cholestatic liver injury onset and progression.

Autoimmune Hepatitis (AIH) is a kind of autoimmune diseases. In AIH, loss of tolerance against liver autoantigens causes elevated serum aminotransferase levels, presence of non-organ-specific autoantibodies with unknown function, hyperglobulinemia, progressive destruction of the hepatic parenchyma, and development of hepatic fibrosis (81). Recent studies have indicated that the NLRP3 inflammasome drives pathogenesis of concanavalin-A (ConA)-induced hepatitis. Liver pathology was related to elevated levels of NLRP3, IL-1β, caspase-1 and pyroptosis-mediated cell death (82). Moreover, ConA could induce activation of the NLRP3, caspase-1 and IL-1β production in macrophages in vitro. IL-1β levels were elevated in AIH patients and correlated with aggravation of hepatitis (83). NLRP3 inflammasome also participates in Trichloroethene (TCE) -induced AIH (84). Using an interleukin-1 receptor (IL-1R) antagonist could suppress hepatic inflammation of AIH by diminishing NLRP3 inflammasome activation. The miR-223 negatively regulates NLRP3 expression (85). The application of exosomes containing miR-223 decreases NLRP3 and caspase-1 expression and promotes AIH to abate (86). Collectively, these findings demonstrate that the NLRP3 inflammasome signaling pathway plays a crucial role in the initiation, progression, and development of AIH, and inhibition of the NLRP3 inflammasome signaling pathway also offers a new and appropriate therapeutic strategy for the treatment of AIH.

Hepatic fibrosis (HF) is vigorous as well as a reversible process of wound healing, where quiescent hepatic stellate cells (HSCs) proliferate and transdifferentiate into myofibroblasts which are responsible for depositing extracellular matrix (ECM) proteins, leading to tissue scarring. HF is a crucial step and inevitable stage in transforming various chronic liver diseases into cirrhosis and liver cancer (87). In the progression of HF, the aberrant regulation of inflammation is a prominent driving factor. NLRP3 inflammasome plays an essential role in the fibrosis process of liver tissues (88). Inzaugarat, Maria Eugenia et al. found that NLRP3 inflammasome activated in HSCs directly contributes to HF development without the presence of inflammatory infiltrates (89). Transgenic mice expressing constitutively active NLRP3 showed severe hepatocyte pyroptosis, inflammation, and fibrosis (90). It also has been found that the NLRP3 inflammasome participates in HF caused by schistosomiasis (91). Deficiency or inhibition of NLRP3 inflammasome can improve HF, hepatic inadequacy, liver inflammation, granuloma, and hepatosplenomegaly caused by schistosomiasis (7, 92). Many factors can activate the NLRP3 inflammasome, leading to the secretion of IL-1β and IL-18, and induce HF (52). For example, Androgen, an activator of the NLRP3 inflammasome, can aggravate liver damage in carbon tetrachloride (CCL₄)-induced HF mice model (93). Galectin-3 is a multifunctional glycoprotein that promotes infiltration by mononuclear cells by enhancing the production of NLRP3 inflammasome and IL-1β, which promotes granuloma and HF (94). Correspondingly, many factors can delay or reverse HF by inhibiting NLRP3 inflammasome activation (95, 96). Overall, these findings strongly indicate that NLRP3 inflammasome plays a key role in HF, the mechanisms by which the NLRP3 inflammasome regulates fibrogenesis are not well understood. Further, it remains unclear whether IL-18 promotes or inhibits fibrogenesis (97) and more research is required.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. It frequently develops in the context of chronic hepatitis and cirrhosis and is the third leading cause of cancer death worldwide (98). The presence of a chronically inflammatory microenvironment is one of the factors that can promote tumorigenesis and metastasis (99). The overexpressed NLRP3 in HCC indicated worse overall survival. In HCC, inhibition of NLRP3 promotes the killing effect of T cells to cancer cells by repressing the expression of immune checkpoints (100). A study found that a deletion of NLRP3 suppresses cancer development and metastasis of HCC cells in vitro and in vivo (97). However, it was also demonstrated that a deficiency in NLRP3 inflammasome expression is involved in HCC progression, which suggests that the NLRP3 inflammasome has a protective role against the development of HCC (101). These opposite conclusions may be due to the different functions of the NLRP3 inflammasome. It is important to note that the NLRP3 inflammasome represents the first line of defense against pathogenic microbes within the innate immune system. When the body is exposed to a pathogenic insult, the NLRP3 inflammasome acts as a guard and is assembled and activated to elicit hepatic inflammation and return the system to homeostasis. However, chronic persistent inflammation and inflammasome abnormal activation induces massive cell death, and NLRP3’s homeostatic threshold could be exceeded, then causing compensatory hepatocyte proliferation and HCC.

Chronic pancreatitis (CP) is a syndrome caused by genetic and environmental factors (102) and characterized by inflammatory cell infiltration, progressive organ atrophy, and disorder of collagen deposition (103). There is increasing evidence that NLRP3 inflammasome plays a vital role in the inflammatory response of pancreatic tissues. Zhang G et al. observed that NLRP3 activation mediates caspase-1 activation and promotes the activation of pro-IL-1β and pro-IL-18, which are key pro-inflammatory cytokines in the pathological mechanism of CP (104). Through P2X7R inhibitor, Zhang GX inhibited the secretion of IL-1β and IL-18 which were dependent on NLRP3 to reduce chronic pancreatic inflammation and fibrosis, which confirms the pivotal role of the NLRP3 pathway in the occurrence and development of pancreatitis (105). Furthermore, NLRP3 inflammasome also participates in the fibrotic process of CP (106). Abnormal activation of pancreatic stellate cells (PSCs) releases a vast amount of ECM containing type I collagen (Col I), type III collagen (Col III), and fibronectin (FN), which plays a significant role in the extensive fibrosis of pancreatic tissues (107). Li CX et al. verified the causality between NLRP3 inflammasome and the abnormal activation of PSCs. They observed that the NLRP3 inflammasome is directly involved in activating PSCs in vivo and in vitro. Inhibiting NLRP3 suppresses the activation of PSCs and ECM deposition, thus alleviating pancreatic fibrosis (108). In conclusion, the above data reveals that NLRP3 inflammasome has a pro-inflammatory and pro-fibrogenic role in CP.

Acute pancreatitis (AP), one of the fatal diseases of the gastrointestinal tract, is a kind of aseptic inflammation characterized by pancreatic enzyme activation and partial pancreatic inflammatory reaction. Studies have confirmed that while pancreatic inflammation may be initially triggered by intra-acinar events such as trypsinogen activation, it ultimately depends on the subsequent immune responses induced by the activation of inflammasome of the innate immune system. Neutrophils and macrophages from pancreatic acinar cells (PACs) recognize PAMPs and DAMPs in the damaged pancreatic tissues of AP (12), increase NF-κB and NLRP3 inflammasome expression and inducie the release of downstream inflammatory factors, which eventually promote the damage and inflammation of pancreatic tissues (109). IL-1β and IL-18 have been recognized as markers of severity of AP (110). In contrast to other cytokines, IL-1β and IL-18 are synthesized as precursor proteins and require cleavage in order to be biologically active. A key component of this process is the NLRP3 inflammasome. It has been demonstrated by Hoque and Mehal that the NLRP3 inflammasome is substantially activated during AP, and that components of this inflammasome are crucial for the development of total pancreatic injury. An experimental model of cerulein-induced AP in mice showed significant reductions in edema and systemic inflammation when caspase-1, ASC, and NLRP3 were not present (12). Wang, J, etc. reported that the activation of NLRP3 inflammasome and promotion of caspase-1-induced pyroptosis aggravate AP (111). Overactivation of NLRP3 inflammasome had also been found to contribute to the pathomechanism of AP by exacerbating intestinal dysfunctions (112). Recently, a meta-analysis demonstrated that the inhibition of NLRP3 inflammasomes significantly decreased pancreatic histopathological scores, serum amylase levels and lipase levels as well as circulating levels of inflammatory cytokines and reduced the severity of acute lung injury and acute intestinal injury as a result of AP. It has been recognized that the NLRP3 inflammasome plays a significant role in the pathogenesis and complications of AP (113).

Approximately 20% of AP patients suffer from acute exacerbation, pancreatic necrosis, systemic inflammatory response, and multiple organ failure, which candevelop into severe acute pancreatitis (SAP) (114). SAP is a common acute disease in the digestive system, with the characteristic of rapid progression, which might cause multi-organ complications. Previous studies have confirmed that the fast production and release of a large number of inflammatory cytokines damage the pancreas and other organs (115). This process plays a crucial role in the pathological process of SAP. Sendler M et al. observed that mRNA content of NLRP3 and protein content of NLRP3 inflammasome were significantly increased in tissues of SAP mice, and deletion of NLRP3 reduced neutrophil maturation and macrophage infiltration, thereby reducing immune/inflammatory responses of the body (116). A significant reduction in systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome was observed in mice with severe pancreatitis that were inhibited by NLRP3 (116). By comparing the pathological tissues of (NLRP3 +/+) and (NLRP3 -/-) WT mice, it was found that knock-out NLRP3 plays a crucial role in alleviating SAP-related inflammation and lung injury. Similar results were confirmed in SAP mice models treated with NLRP3 inhibitors (117). Overall, the above findings suggest that SAP and its complications were characterized by activation of NLRP3 inflammasome. Most importantly, these results provide a potential molecular target for treating pancreatic disease.

A tumour of the digestive system that is highly malignant and highly invasive is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, accounting for about 90% of pancreatic cancer (118). Pancreatic ductal adenocarcinoma (PDAC) is a substantial global threat to human health. Previous studies have confirmed that inflammatory injury is a significant risk factor for PDAC. Romero JM et al. observed up-regulation of NLRP3 inflammasome pathway by RNA sequencing and whole-genome sequencing in cancer tissues of patients with primary resected PDAC and PDAC liver metastases (119). Similar results were obtained in experiments, in which up-regulation of NLRP3 inflammasome expression was observed in platelets of mice models with primary PDAC (120). Daley D et al. further verified the indispensable role of the NLRP3 inflammasome in the pathological mechanism of PDAC by observing the protective effect of pharmacological inhibition or deletion of NLRP3, ASC, and caspase-1 in PDAC mice models (121). Findings identify a new modality for immune evasion in PDAC that depends on IL-1β production by tumor cells through TLR4-NLRP3 inflammasome activation. IL-1β is an essential component of PDAC’s immune toleranc (122). NLRP3 plays a significant role in establishing the microenvironment surrounding the PDAC tumor by modulating the expression of IL-1β (123).

Inflammatory bowel disease (IBD) is a chronic, recurrent gastrointestinal disorder that does not present structural or biochemical abnormalities, and it is associated with abdominal pain, distention of the abdomen, changes in the bowel habits, and changes in stool characteristics. The etiology is caused by environmental factors, infectious agents, and genetic susceptibility, including ulcerative colitis (UC) and crohn’s disease (CD). Clinical evidence uncovered that upregulation of NLRP3 and IL-1β were observed in UC patients (124) and CD patients (125). It was also shown that NLRP3 inflammasome and downstream effector expression including IL-1β are increased in inflamed mucosa of IBD patients and correlate with disease activity. Inflammasome gene expression increased with the abundance of immature intestinal macrophages (126). Research demonstrates that NLRP3 acts as a molecular switch by shifting local immune cells toward an inflammatory phenotype via IL-1β (122). Experiments observed the effects of NLRP3 deletion or inhibition or blocking oligomerization on the development of intestinal inflammation and concluded that the overactivation of NLRP3 inflammasome and its major cytokines promotes the development of IBD (127–131). It was also found that mice genetically deficient in miR-223 display markedly exacerbated experimental colitis, as indicated by increased immune infiltration (neutrophils and monocytes), hyperactivated NLRP3, and IL-1β release. Meanwhile, nanoparticle delivery of miR-223 mimetics can constrain the level of NLRP3 activation, provides an early break, limiting cytokine-mediated immune disequilibrium, and attenuate experimental IBD (4). There is, however, debate regarding whether the NLRP3 inflammasome contributes to IBD in a beneficial or pathogenic manner. A number of studies have shown that the NLRP3 inflammasome plays a key role in regulating mucosal immune responses as well as intestinal homeostasis (61). NLRP3-induced IL-18 is required for the proliferation of intestinal endothelial cells. Hence, it has been speculated that the appropriate activation of the NLRP3 inflammasome in the intestinal epithelial cells contributes to the maintenance of internal environmental stability and integrity of the barrier. This discovery could be related to the compensatory response of the NLRP3 inflammasome stimulating the proliferation of epithelial cells (132). It has identified that early activation of NLRP3 in intestinal epithelial cells limits pathogen colonization and prevents subsequent intestinal inflammation (133). Reports are suggesting that IL-1β and IL-18 induced by the NLRP3 inflammasome confer protection against colitis and colitis-associated tumorigenesis (134–136). Moreover, hyperactive NLRP3 maintains gut homeostasis by inducing regulatory T cells (Tregs) (137). Studies also found the deficiency of NLRP3 inflammasome composition increases susceptibility to experimental colitis in mice (134, 138, 139). NLRP3 also plays a protective role in the probiotic-based therapy of colitis (140). These controversial outcomes may be due to the experimental protocols, different facilities, variable effects of microbiota, and the genetic background of mice. IBD therapeutic approaches will be inspired by further studies on the molecular regulation of the NLRP3 inflammasome activity during inflammation.

More and more evidence focus on autophagy and NLRP3 inflammasome interaction in the development of IBD in its extended form. Autophagy has an excellent negative regulatory effect on the activation of NLRP3 inflammasome, including removal of the sources of endogenous activation of NLRP3 inflammasome, ROS inhibition, removal of damaged mitochondria, and selective degradation of inflammasome components (14, 141). NLRP3 inflammasome signal also negatively regulates autophagy. NLRP3 may be a binding partner of the inhibitors of autophagy. In IBD mice models, NLRP3 binds to mTOR (an autophagy inhibitor) to promote the phosphorylation of mTOR and inhibite autophagy (142). Quach C et al. found NLRP3 inflammation hyperactivation in an autophagy inhibition mouse model. NRLP3 inflammasome inhibition also might be a strategy that promotes the activation of autophagy in an efficient manner. Collectively, the NLRP3 inflammasome activation dynamically interacts with autophagy during the development of intestinal inflammation (143), and the balance between autophagy and the NLRP3 inflammasome helps to maintain the homeostasis of the host. These findings also raised the possibility of using NLRP3 inhibitors that induce autophagy or autophagy activators that inhibit inflammasome as potential therapeutic strategies for IBD treatment.

To further explore the pathological mechanism of IBD from the perspective of gene polymorphism, the role of NLRP3 inflammasome-related genes in IBD has been researched. ZhouL et al. found that NLRP3 is encoded by RS772009059 (R779C) in 3 patients with early-onset IBD. In dextran sulphate sodium (DSS)-induced models of acute colitis, R779C promotes the activation and apoptosis of the NLRP3 inflammasome in macrophages and is positively correlated with the incidence of severe diseases (144). Studies indicate that some genotypes of the NLRP3 inflammasome may be associated with the affectability of patients with IBD and could represent biomarkers for the evaluation of IBD severity. A Swiss cohort study found that three NLRP3-related single nucleotide polymorphisms (RS10733113, RS55646866, rs4353135) were negatively related to CD (145). Moreover, some negative results were found (146). In short, the gene polymorphism of the NLRP3 inflammasome will provide new insights into IBD pathogenesis. Different NLRP3 gene therapy methods are waiting to be developed in the future. But the role of gene polymorphism of NLRP3 inflammasome in IBD has not yet been fully discovered. More research is needed in the future.

Colorectal cancer (CRC) is the third common malignancy and the second common cause of death from malignancies (147). Chronic gut inflammation is a critically predisposing factor for the development of CRC. Shi F et al. observed that NLRP3 expression is elevated in human tissues of CRC (100 cases) and mice models of colorectal adenocarcinoma. The elevated levels of NLRP3 are correlated with distant metastasis, vascular infiltration, and positive lymph nodes. In addition, the survival analysis of kaplan-Meier showed that high expression of NLRP3 was associated with a lower 5-year survival rate and lower 10-year survival rate (148). These results might elucidate that NLRP3 is an independent risk factor for CRC prognosis. Similarly, Marandi Y et al. compared the cancer tissues and adjacent normal tissues of 43 patients with CRC and concluded that the development of CRC was related to the NLRP3 inflammasome activation (149). NLRP3 activation was also found to accelerate the rate of cell migration of CRC. Blocking the NLRP3 signaling suppressed CRC cell migration in vitro, and metastatic ability in vivo (150). The NLRP3 inflammasome regulates the activation of caspase-1. Activation of caspase-1 enhances the secretion of IL-1β and IL-18. IL-1β and IL-18 lead to the infiltration of more immune cell, result in the generation and maintain an inflammatory microenvironment of CRC (151). Interestingly, the pro-inflammatory and carcinogenic effect of dietary cholesterol in CRC (152) and the carcinogenic effects of porphyromonas gingivalis in CRC are also related to NLRP3 inflammasome overactivation (153). Whereas the inflammasome complex is also a protectant in the intestinal epithelium. In research, NLRP3 deficient mice showed an increased diarrhea, rectal bleeding and mortality (135). The anti-tumor effect of IL-18 blocks tumors development as well as inhibits angiogenesis and may induce epithelial cell recovery (136). Furthermore, IL-18 can reduce cell proliferation in the intestinal epithelium at the tumor zone in the colitis remission phase (154). There are studies revealed that protective effect of pyroptosis mediated by NLRP3 on CRC. Tang Z et al. confirmed in vivo and in vitro experiments that NLRP3 inflammasome mediated pyroptosis could inhibit the proliferation, migration, and invasion of CRC cells (155). NLRP3 inflammasome has also been reported to enhance NK cell tumoricidal function mediated by IL-18 by inhibiting CRC metastatic growth (156). It has been found that in the intestinal mucosa with high expression of antigen, inflammation with low levels is indispensable for the harmony between the immune system and the microbiota and helps to maintain homeostasis (157). To sum up, controversy remains and some people believe that the NLRP3 inflammasome is a double-edged sword in the development of CRC (158, 159). While long-term effects of the NLRP3 inflammasome activation, and inflammatory reaction are associated with poor outcomes, mild inflammation may be beneficial.