key: cord-0907627-ta07bho2
authors: Antushevich, Hanna
title: Interplays between inflammasomes and viruses, bacteria (pathogenic and probiotic), yeasts and parasites
date: 2020-09-22
journal: Immunol Lett
DOI: 10.1016/j.imlet.2020.09.004
sha: e84b71a362eede2459bb011df848a5f961359f82
doc_id: 907627
cord_uid: ta07bho2

In recent years, scientists studying the molecular mechanisms of inflammation have discovered an amazing phenomenon – the inflammasome – a component of the innate immune system that can regulate the functional activity of effector cells during inflammation. At present, it is known that inflammasomes are multimolecular complexes (cytosolic multiprotein oligomers of the innate immune system) that contain many copies of receptors recognizing the molecular structures of cell-damaging factors and pathogenic agents. Inflammasomes are mainly formed in myeloid cells, and their main function is participation in the cleavage of the pro-IL-1β and pro-IL-18 cytokines into their biologically active forms (IL-1β, IL-18). Each type of microorganism influences particular inflammasome activation, and long-term exposure of the organism to viruses, bacteria, yeasts or parasites, among others, can induce uncontrolled inflammation and autoinflammatory diseases. Therefore, this review aims to present the most current scientific data on the molecular interplay between inflammasomes and particular microorganisms. Knowledge about the mechanisms responsible for the interaction between the host and certain types of microorganisms could contribute to the individuation of innovative strategies for the treatment of uncontrolled inflammation targeting a specific type of inflammasome activated by a specific type of pathogen.

infections, the appearance of allergies and autoimmune diseases. The leading role of inflammasomes is to activate pro-inflammatory cytokine synthesis and pyroptosis to remove harmful stimuli from the organism. Despite the beneficial effects of inflammation, this process should be tightly regulated due to excessive activation of inflammasomes leading to overproduction of inflammatory cytokines and the appearance of the unregulated inflammatory process that can cause chronic inflammation and autoinflammatory diseases (e.g., familial

Mediterranean fever (FMF), hyperimmunoglobulin D syndrome, Crohn's disease, osteoporosis, pulmonary manifestations, etc.) [6] [7] [8] . It should be underscored that during autoinflammatory disease, the main role is played by native immunity and not adaptive immunity, as observed in autoimmune diseases. Recent scientific data show that pharmacological inhibition of inflammasome expression in some diseases may lead to an immunosuppressive reaction and thus prevent tissue destruction [9] .

Each type of microorganism differentially influences inflammasome activation, and the duration of exposure to viruses, bacteria, yeasts, or parasites could induce uncontrolled inflammation. Therefore, this review aims to present the most current scientific data concerning the molecular interplay between inflammasomes and particular microorganisms. Knowledge of the mechanisms responsible for interactions between the host and pathogen could contribute to the individuation of innovative strategies for the treatment of uncontrolled inflammation and autoinflammatory diseases targeting a specific type of pathogen.

Multiple scientific reports have demonstrated that viruses entering the body activate an innate immune response in which inflammasomes play a crucial role in pathogen destruction [10] [11] [12] .

To control infection, the immune system detects pathogens in multiple ways. There are two systems of first-line of defense against viruses: the production of Type I interferons and the production of the cytokines IL-1β and IL-18 by inflammasomes. Type I interferons promote an antiviral state in the infected host, whereas cytokines have antiviral effects by inducing inflammatory processes and modulating adaptive immune responses in the organism [13] .

The influenza A virus (IAV) belongs to the Orthomyxoviridae family, which contains negativesense RNA as its genome. This virus infects and replicates in epithelial cells of the respiratory tract, and the disease severity is regulated by both virus-encoded and host factors and is associated with a high level of morbidity and mortality. The significant factors modulating the pathogenesis of IAV are epithelial damage and lung inflammation [14] . Several intracellular J o u r n a l P r e -p r o o f signaling cascades regulate inflammation and cell death in IAV infection [15] . For example, Ichinohe et al. [16] infected bone marrow-derived macrophages (BMM) with influenza A and B virus in vitro discovered that influenza viruses activate signal 1 through stimulation of macrophages and DCs via TLR7, resulting in the synthesis of pro-IL-1β and pro-IL-18. Upon infection, virally encoded M2 is expressed in the secretory compartment, including TGN.

Additionally, the ion channel activity of M2 enables H + export from acidified Golgi and thereby is a trigger for signal 2 required for the formation of the NLRP3 inflammasome complex. The authors also underscored that the M2-His37Gly mutant, which is capable of transporting Na + and K + , may induce elevated amounts of inflammasome activation, and imbalances in the concentrations of other cations which may signal the activation of inflammasomes [16] . al. [10] discovered, that HIV-1 could activate the 'priming' signal for NLRP3 inflammasome activation through NF-κB signaling, leading to IL-1β secretion in the presence of specific NLRP3 inflammasome activators such as ATP, nigericin, silica, alum, and MSU. In that experiment, the authors noticed that when HIV-1 was used as the priming and second signal, J o u r n a l P r e -p r o o f the MDMs were unable to secret IL-1β and concluded that early phases of HIV-1 infection were unable to induce the second signal for NLRP3 inflammasome activation [10] . In another study were reported that HIV could activate the inflammasome in monocytes and macrophages in an infection-independent process requiring clathrin-mediated endocytosis and viral recognition by distinct endosomal TLRs. It was also discovered that HIV is not required for inflammasome activation of TLR7 [20] . Moreover, peripheral blood CD14⁺⁺CD16⁻ monocytes of HIV-1infected persons release large intracellular protein aggregates of the inflammasome adaptor ASC (PYCARD)) into the bloodstream, which can contribute to inflammasome activation [21] .

Furthermore, inflammasomes play a significant role in HIV-associated neuroinflammation. For example, in in vitro experiments on human primary neurons (HPNs) and microglial cells (HFMG) collected from healthy patients, it was discovered that treatment of the cells with HIV ssRNA40 (specific GU-rich single-stranded RNA from the HIV long terminal repeat region) activates the NLRP3 inflammasome and increases the expression and extracellular secretion of pro-inflammatory cytokines (IL-1β, IL-18) and neurotoxic cytokines (TNF-α, IL-1α, C1q). HIV ssRNA40 causes a blockade of autophagy/mitophagy-mediated negative regulation of NLRP3 inflammasome activity with the release of inflammatory cytokines, caspase-1 activation, and pyroptotic microglial cell death [22] . Another report has shown that HIV-1 induces the expression of NLRP3 inflammasome and IL-1β secretion in dendritic cells from healthy individuals but not HIV-1-infected patients, suggesting that inflammasome activation contributes to disease progression [23] . There is also evidence that since the HIV-1 genome contains two RNA molecules that in turn are reverse-transcribed into a cDNA molecule, the NLRP3 inflammasome may be activated in response to both RNA and DNA [11] .

The hepatitis C virus (HCV) is an enveloped, single-stranded RNA-containing virus with a virion size of 30-60 nm belonging to the Flaviviridae family that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In infected hepatocytes, hepatitis C virus blocks viral poly-U/UC PAMP/RIG-I-mediated production of type 1 and 3 interferons through the action of the viral NS3/4A protease, which targets and cleaves the innate immune adaptor molecules mitochondrial antiviral signalling protein (MAVS) to destroy the intracellular antiviral defense system [24] . Multiple scientific reports have shown that in patients infected with HCV, inflammasomes not only participate in virus eradication but cause chronic inflammation and liver fibrosis and can participate in hepatocellular carcinoma (HCC) [12] .

A study on THP-1 cells (model of hepatic macrophages) showed that TNF-α serves as a priming factor in hepatic macrophages, leading to NFκB activation and pro-IL-1β production; mainly the HCV core protein can activate the NLRP3 inflammasome. Viral core protein directs J o u r n a l P r e -p r o o f intracellular calcium mobilization to impart NLRP3 inflammasome assembly through activation and signalling of phospholipase-C, leading to the synthesis of bioactive IL-1β from macrophages, thus establishing the hepatic inflammatory environment [24] . These data show that the NLRP3 inflammasome and IL-1β induce liver inflammation and may be used as a target for treating liver disease induced by HCV. It should also be noted that in patients suffering from HCC, inflammasomes suppress HCC cell proliferation and differentiation, indicative of positive roles of inflammasomes against HCC [12] .

The Enterovirus 71 (EV71 or EV-A71) is a single-stranded RNA (ssRNA) virus of the genus Enterovirus in the Picornaviridae family. EV71 usually infects children under the age of 5 years. EV71 mainly causes hand-foot-and-mouth disease, and it can also cause brain stem encephalitis, aseptic meningitis, and other nervous system disorders [25] . Scientific reports have shown that in the early phase of infection, EV71 activates the NLRP3 inflammasome in infected mice and the human monocytic cell line THP-1, and it causes an increase in IL-1β, IFN-γ, TNF-α, and IL-6 secretion supporting the protective role of the NLRP3 inflammasome against EV71 infection. In the later phase of THP-1 cell infection, in contrast, the toxic EV71 viral proteases 2A and 3C could antagonize inflammasome activation by cleavage of NLRP3 protein at the G493-L494 or Q225-G226 junction, thereby inhibiting inflammasome activation [26] . Additionally, EV-A71 3D protein, an RNA-dependent RNA polymerase (RdRp), interacts with the leucine-rich repeat domain (LRR) of NLRP3 to facilitate assembly of the inflammasome complex [27] . In addition to the NLRP3 inflammasome, the AIM2 inflammasome also plays an important role in limiting EV-A71 replication in encephalomyelitis patients. In the neuroblastoma cell line SK-N-SH, cells transfected with EV-A71 RNA showed increased AIM2 gene expression. In contrast, silencing of AIM2 in SK-N-SH cells resulted in decreased activation of IL-1 and increased viral replication upon EV-A71 infection [28] .

(HHV) family. EBV can replicate in B-lymphocytes, epithelial cells, or dendric cells and is associated with a variety of tumors, including Burkitt lymphoma, immunocompromiseassociated lymphomas, and nasopharyngeal cell carcinoma [29] . EBV-positive endemic BL cell line HH514-16 and peripheral blood mononuclear cells (PBMC) isolated from the blood of patients with NOMID syndrome had heterozygous germline mutations in their NLRP3 gene which showed assembly of the TXNIP−NLRP3 inflammasome and activation of procaspase-1 and active caspase-1 during lytic growth. Inflammasome-activated caspase-1 then led to a partial loss of KAP1/TRIM28 to turn on the expression of the viral replication switch protein within a subpopulation of cells [30] . EBV may also infect primary human monocytes, and in in J o u r n a l P r e -p r o o f vitro experiments on the THP-1 cell line and primary human monocytes discovered that EBV could induce caspase-1-dependent IL-1β production mainly to activate the AIM2 inflammasome [31] . [33] . The genetic sequence of SARS-CoV-2 shows close sequence homology to the SARS-CoV (approximately 76% amino acid sequence identity) [34] . It is known, that MERS-CoV enters into human cells using the dipeptidyl peptidase 4 (DPP4 or CD26) receptor which is broadly expressed on alveolar, intestinal, renal, hepatic and prostate cells as well as on activated leukocytes [35] . In the case of SARS-CoV, S proteins bind to the angiotensin-converting enzyme 2 (ACE2) which is present on nonimmune cells (endothelial, respiratory and intestinal epithelial cells, alveolar monocytes/macrophages, cerebral neurons, kidney cells) [36] .

It should be noted that the binding affinity of SARS-CoV-2 with ACE2 seems stronger than SARS-CoV and down-regulation of ACE2 function causes lung damage during SARS-related pneumonia [37] . Therefore, an increasing ACE2 level in respiratory epithelial cells is seriously considered as a novel promising therapeutic in SARS treatment. Furthermore, SARS-CoV-2 J o u r n a l P r e -p r o o f for S-protein priming and facilitating cell entry following receptor binding has evolved to utilize a wide array of host proteases including transmembrane protease serine 2 (TMPRSS2), elastase, furin, trypsin, factor X, cathepsin L and cathepsin B [38, 39] . When SARS-CoV-2 enters into healthy cells decreases the amount of ACE2, which leads to an increase of angiotensin II level in the blood. It was found out that angiotensin II triggers the inflammatory pathway of NF-κB and IL-6-STAT3 in endothelial and epithelial cells, but not in immune cells what leads to the development of a cytokine storm (hyperproduction of cytokines) that ultimately result in the acute respiratory distress syndrome (ARDS) [37, 39] . Moreover, patients occur a secondary reaction -immunodeficiency, which contributes to the development of opportunistic bacterial and mycotic infections and septic shock, which then may lead to multiple organ dysfunction syndrome (MODS) [39] . Clinical reports show that both mild and severe forms in SARS-CoV, MERS-CoV, and SARS-CoV-2 infections cause the activation of myeloid and lymphocyte subsets in the blood that leading to the cytokine storm. During cytokine storm changes in cytokines secretion are observed, particularly IL-6, IL-1β, IL-10, TNF, IFN-γ, GM-CSF, IP-10 (IFN-γinduced protein 10), IL-17, MCP-3, and IL-1ra. It was noted, that the serum SARS-CoV-2 viral load is closely associated with IL-6 levels in critical patients and this cytokine may contribute to the development of ARDS in COVID-19 patients. Also, in both SARS and MERS patients, activation of CCR4+ CCR6+ Th17 cells takes part in a cytokine storm [40] . Additionally, inflammasomes play an essential role in cytokine release. It is known, that innate immune system and optimal activation of inflammasomes play an important role in antiviral host defenses, but inflammasomes overactivation often lead to uncontrolled inflammation and pathological tissue injury during infection. Several studies have reported that during SARS-CoV, MERS-CoV or SARS-CoV-2 infection aberrant activation of NLRP3 inflammasome is observed which contribute to cytokine storm and pyroptosis in target cells [41] .

What concerning the signalling pathways of NLRP3 inflammasome activation in response to SARS-CoV infection it is known that SARS-CoV E protein induces Ca2+ leakage to the cytosol from Golgi storage and ORF3a protein induce K+ efflux at the plasma membrane to the extracellular spaces [41, 42] . The imbalance in the ionic concentration in the cells, generated by damaged mitochondria ROS lead to NLRP3 inflammasome activation. Also, ORF3a viroporin protein helps inflammasome assembly through TRAF3-mediated ubiquitination of ASC. While

ORF8b viroporin protein directly interacts with the leucine-rich repeat of NLRP3 to stimulate its activation independent of ion channel activity. Active NLRP3 induces IL-1β and IL-18 secretion, and pyroptosis [41, 43] .

The signalling pathways of inflammasomes activation in response to SARS-CoV-2 infection is still under research. Scientists present different signalling pathways that may lead to NLRP3 inflammasome activation. Up to date, it is known that activation of the renin-angiotensinaldosterone system (RAAS) leads to elevated levels of angiotensin II, which, after binding to the AT1 receptor, triggers the NLRP3 inflammasome in cells [44] . Also, the SARS-CoV-2 virus N proteins may activate the ComC in an MBL-MASP-2-dependent manner. In turn, the ComC cleavage fragments (the C3a and C5a anaphylatoxins), and C5b/C9 membrane attack complex (MAC), can trigger the NLRP3 inflammasome in cells. Moreover, there is the supposition that SARS-CoV-2 can directly activate the NLRP3 inflammasome in target cells by binding to ACE2 only via the spike protein [44] . Active NLRP3 initiates activation caspase-1, which causes the transformation of pro-IL-1β and pro-IL-18 cytokines into IL-1 β and IL-18, respectively and by creating gasdermin D pore channels in cell membranes lead to cell death by pyroptosis [3] .

Based on the strong inflammatory potential of the NLRP3 inflammasome during infections caused by MERS-and SARS-CoVs, inhibition of the NLRP3 inflammasome activity may attenuate the cytokine storm and be a therapeutic target in the treatment of tissue inflammation in SARS patients [33, 41] .

Several studies have demonstrated that infection of cells with pathogenic bacteria induces the assembly of inflammasome complexes and IL-1β and IL-18 secretion. During host defense against bacterial infection, a prominent role play pattern recognition receptors (PRRs). There are two major classes of PRRs: first-class -PRRs that include membrane-bound Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), and second class -non-membrane bound intracellular receptors such as the AIM2-like receptor (ALR), RIG-I-like receptor (RLR), nucleotide-binding protein domain and leucine-rich repeat-containing (NLR) proteins.

Activation of these receptors also upregulates inflammasome activity that takes part in controlling replication and dissemination of microbial pathogens in the organism [13] .

Pathogenic microorganisms, in turn, evolve virulence factors aimed to antagonize inflammasome pathways and in this way, increase their ability to survive in the host organism and cause disease. Competition occurs between the pathogen and host to control pyroptosis and pro-inflammatory cytokine secretion, and the outcome dictates the life or death of the host [13, 45] .

Helicobacter pylori (H. pylori) is a Gram-negative, helically shaped, microaerophilic bacterium that colonizes the human stomach and is a leading cause of certain types of human gastric diseases such as chronic gastritis, gastric ulcers and gastric carcinomas [45] . Pachathundikandi et al. [46] demonstrated that infection of mice by H. pylori leads to stimulation of the expression of the NLRP3 inflammasome. Analysis of bacterial pathogenicity factors and molecular mechanisms of inflammasome activation shows that by engagement of the immune receptor TLR2, H. pylori triggers NLRP3 and caspase-1 stimulation of IL-1β production.

H. pylori also stimulates TLR9 and TLR10 and induces the secretion of IL-8 and TNF. Highers in this way may induce gastric carcinomas [45] .

of Mycobacterium species that can cause tuberculosis in humans and animals. In 2016, Wei et al. [47] found that M. tuberculosis infection of the human acute monocyte leukaemia cell line THP-1 could promote NLRP3 activation and inflammatory cytokine secretion. The authors discovered that NLRP3 activation was regulated by DNA methylation modification, and DNA methylase Sss I methylation decreased NLRP3 promoter activity. These data suggest that during M. tuberculosis infection, DNA methylation is involved in NLRP3 inflammasome activation [47] . Clinical M. tuberculosis isolates compared to the laboratory strain H37Rv have been shown to induce lower IL-1β release than H37Rv, suggesting different inflammasome activation abilities. IL-1β maturation involves NLRP3, AIM2, and an additional unknown sensor. Pharmacological blockade of NLRP3 with MCC950 leads to a reduction of bacterial survival [48] .

negative bacteria that is predominately found in the gut lumen and causes gastroenteritis in humans and animals. S. typhimurium invasion of the mucosa can lead to its migration to J o u r n a l P r e -p r o o f mesenteric lymph nodes, liver, and spleen, causing a life-threatening infection. Its toxicity is due to an outer membrane consisting largely of lipopolysaccharides that protect the bacteria from the environment [49] . typhimurium [53] . canis, which infects dogs [58] . In peripheral blood samples obtained from patients with acute brucellosis, no effect on caspase-1 and NLRP3 was observed, but an increase in serum IL-18, IFN-γ levels and AIM2 and NLRC4 inflammasome expressions was documented in comparison to healthy controls [58] . Gomes et al. [59] also found that NLRC4 did not need to induce caspase-1 activation and further secretion of IL-1β by B. abortus in macrophages, whereas AIM2, which senses Brucella DNA, and NLRP3 were required for caspase-1 activation and IL-1β secretion, and AIM2 knockout mice were more susceptible to Brucella infection than wildtype control mice [59] . Pretreatment of B. abortus-infected alveolar epithelial cells with a specific caspase-1 inhibitor leads to a reduction of IL-1β production in cells, which may suppress inflammation in the lung [60] . Overall, these data suggest that multiple ASCdependent inflammasomes participate in host defense against Brucella infection. 

Probiotic bacteria have no impact on inflammasome activation and pro-inflammatory cytokine synthesis in healthy individuals, but probiotics may regulate inflammasome activation in organisms that have previously experienced some degree of inflammation due to pathogenic bacterial infection [64, 65] . These data suggest that L. rhamnosus has antiviral potential in human macrophages [70] . [72] .

The innate immune system is also the first line of defense against fungal pathogens. Pattern recognition receptors recognize fungal particles and initiate cellular responses and killing mechanisms to destroy the pathogenic yeasts. Upon organism entry, yeasts can induce often recurring and equally difficult-to-treat mucosal or skin infections. Finally, multiple evidence shows that the host initiates defense mechanisms in numerous fungal pathogens that involve inflammasome activation and robust production of pro-inflammatory cytokines [73] . inflammasome might be a key player in human vulvovaginal disease caused by C. albicans [76] . There is also information that the NLRC4 inflammasome is also essential in protection against C. albicans infection. In bone marrow chimeric mouse models, C. albicans le to upregulation of NLRP3 and NLRC4 expression in the oral mucosa, but in contrast to NLRP3, which decreased the severity of infection when present in either the hematopoietic or stromal compartments, NLRC4 played a significant role in limiting mucosal candidiasis when functioning at the level of the mucosal stroma. These data underscore the tissue-specific role of inflammasomes in innate immune responses against mucosal C. albicans infection [77] .

Aspergillus is a highly aerobic group of conidial fungi that represents over 185 fungal species.

Some invasive pulmonary Aspergillus species can cause infections such as asthma, fibrosis, tuberculosis and other lung infections [78] . In pulmonary aspergillosis in mice caused by fumigatus and simultaneously lacking AIM2 and NLRP3 receptors, hyphal dissemination to lung blood vessels leads to increased susceptibility to infection in comparison to wild type mice.

Interestingly, mice lacking either AIM2 or NLRP3 showed similar susceptibility to hyphal dissemination in comparison to wild type mice. Additionally, AIM2 and NLRP3 activation initiated the assembly of a single cytoplasmic inflammasome platform containing the adaptor protein ASC with caspase-1 and caspase-8, which subsequently caused pro-inflammatory cytokine IL-1β and IL-18 expression [79] . which may influence host defence against P. brasiliensis yeasts [82] .

Numerous scientific data have confirmed the important role of the inflammasomes in the host response to pathogenesis of many parasitic infections [83] . superoxides in livers were observed [90] . In mice suffering from S. japonicum infection, liver fibrosis and high levels of IL-1β, ALT/AST in plasma, and high expression of NLRP3 and NF-κB in liver tissue were observed. Inhibition of NLRP3 inflammasome production alleviated liver inflammation and collagen deposition in infected mice [63] . It was also found that stimulation of mouse hepatic stellate cells HSCs with soluble egg antigen could activate the NLRP3 inflammasome in cells and that NLRP3 activation in the spleen required tyrosine kinase enzyme (Syk), Dectin-1 and JNK [78] . acid, amyloid-β, α-synuclein) ( Table 2) ; chemical irritants (eg. alum, silica, asbestos, UVB irradiation, trinitrophenylchloride, silver nanoparticles) ( Table 3) or pharmacological substances (eg. imiquimod, amodiaquine, nevirapine, propofol, morphine) ( Table 4 ).

The regulation of inflammasome activity involves intracellular and extracellular mechanisms [93] . Intracellular regulators of inflammasome activity include mechanisms associated with the level of calcium and potassium ions in the cell. For example, in cells with a low concentration of potassium and chlorine, dehydration leads to mobilization of calcium ions to initiate TGF-βactivated kinase 1 (TAK1), which leads to deubiquitination of NLRP3 [93, 94] . Also, a change in the concentration of extracellular calcium leads to a decrease in the level of cyclic AMP (cAMP) through inhibition of adenylate cyclase and an increase in the cytoplasmic concentration of Ca2+ through activation of phospholipase C and the production of secondary calcium-mobilizing mediators. Concerning the role of potassium, it is known that activation of NLRP3 and NLRP1B inflammasomes serves as a response to the low concentration of potassium inside cells that promotes ASC assembly. In contrast, a high level of extracellular potassium may block the release of IL-1β after NLRC4 and AIM2 inflammasome formation [9, 94] . Moreover, adenosine triphosphate (ATP) is a NLRP3 inflammasome agonist that can bind to P2X7 receptor and cause the outflow of potassium and formation of pannexin channels in cells, through which it may alter the cell-extracellular signals responsible for inflammasome activity [93, 95] .

In contrast, extracellular upregulation of inflammasome activity can occur through cytokine receptors that activate NLRP3 transcription. In addition, NLRP3 transcription can be triggered by the deubiquitination of NLRP3, which occurs only in response to the stimulation of PRRs [96] . The suppression of inflammasome activity can ensure according to the type of negative feedback in cells or activity of type I interferon (IFN). IFN reduces NLRP3 inflammasome activity through activation of inducible nitric oxide synthase, leading to inhibition of the production of pro-IL 1β and pro-IL-18 [97] . Table 1 . Some pathogenic agents capable of inflammasome activation.

Ligands of TLRs, CLRs, ALR and RLR receptors, NLR proteins Pathogenic virulence factors eg. LPS, LeTx, CagA, VacA, WA, FlaA, by binding to these receptors activate the secretion of an appropriate inflammasome. [98] Cytosolic dsDNA Cytosolic dsDNA from virus, bacteria, or the host itself can activate the AIM2 inflammasome.

[4]

Activate signal 2 of the NLRP3 inflammasome and thereby mediate the activation of the NLRP3-inflammasome.

[17]

HIV ssRNA40 Activates the NLRP3 inflammasome and increases the expression and extracellular secretion of pro-inflammatory cytokines (IL-1β, IL-18) and neurotoxic cytokines (TNF-α, IL-1α, C1q).

[22]

SARS-CoV E, ORF3a and ORF8b viroporin proteins SARS-CoV E induces Ca2+ leakage to the cytosol from Golgi storage and ORF3a protein induce K+ efflux at the plasma membrane to the extracellular spaces. The imbalance in the ionic concentration in the cells, generated by damaged mitochondria ROS lead to NLRP3 inflammasome activation. Also, ORF3a viroporin protein helps inflammasome assembly through TRAF3-mediated ubiquitination of ASC. While ORF8b viroporin protein directly interacts with the leucine-rich repeat of NLRP3 to stimulate its activation independent of ion channel activity. [41, 42] TLRs -Toll-like receptors, CLRs -C-type lectin receptors, ALR -AIM2-like receptor, RLR -RIG-I-like receptor, NLRleucine-rich repeat-containing proteins, IpaH7. 8 

All these molecular patterns trigger the generation of ROS and in the ROS-dependent pathway triggers NLRP3 inflammasome complex formation.

[5]

K + efflux Decrease of intracellular K + concentration in cells is a common trigger for canonical and noncanonical NLRP3 inflammasome activation.

[5]

ATP Extracellular ATP, triggers P2X7-dependent pore formation by the pannexin-1 hemichannel, allowing extracellular NLRP3 agonists to enter the cytosol and formation of NLRP3 inflammasome.

[5]

Cathepsin B Lysosomal permeabilization leads to the release of cathepsin B that triggers the activation of the Nlrp3 inflammasome.

[99]

MSU An increase in intracellular Na + , causing water influx and cellular swelling, which in turn lowers the intracellular K + concentration and induce NLRP3 inflammasome activation.

[100]

Cholesterol crystals Cholesterol crystals cause lysosome rupture, resulting in the release of cathepsin B in cytosol and activate the NLRP3 inflammasome.

[101]

Calcium crystals Calcium phosphate crystals (hydroxyapatite and tricalcium phosphate) through lysosomal rupture, potassium efflux, ROS generation and cathepsin B induce NLRP3 inflammasome activation.

[102]

Uric acid Uric acid released from injured cells via uric acid-dependent pathways can activate the inflammasome NALP3 inflammasome leading to IL-1β production.

[5]

Amyloid-β Amyloid β may directly interact with NLRP3 and initiate inflammasome activation resulting in caspase-1 activation and subsequent maturation and release of IL-1β.

[103], [104] α-synuclein α-synuclein by disrupting the lysosome and facilitating the release of cathepsin B induces NLRP3 inflammasome activation. [103] J o u r n a l P r e -p r o o f DAMPs-danger-associated molecular pattern molecules, HAMPs -homeostasis-altering molecular processes, PAMPspathogen-associated molecular patterns, MSU -monosodium urate, amyloid-βprotein that contribute to Alzheimer's disease, α-synuclein -protein that contribute to Parkinson's disease. Table 3 . Some chemical irritants capable of inflammasome activation.

Alum Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol. The released contents and molecules generated during this process contribute to NLRP3 inflammasome activation.

[102]

Silica Inflammasome activation is triggered by reactive oxygen species, which are generated by a NADPH oxidase upon particle phagocytosis.

[105]

Asbestos NLRP3 inflammasome activation upon asbestos stimulation is dependent on endocytosis and ROS production.

[105]

UVB irradiation UVB irradiation increases intracellular free Ca2+, resulting in the activation of the NALP3 inflammasome [106] TNP-Cl Treatment mice with 0.15 ml 5% TNP-Cl initiate tissue inflammation and activation of Nalp3 inflammasome.

[107]

AgNPs AgNPs stimulate ASC speck assembly formation, caspase-1 activation, and mature IL-1β secretion, indicating the activation of NLRP3 inflammasomes in human THP-1 monocytes and hepatic cells.

[102]

TNP-Cltrinitrophenylchloride, AgNPs -silver nanoparticles. [108]

Amodiaquine and Nevirapine

Reactive metabolites of these drugs cause the release of DAMPs, which in turn activate inflammasomes. [109] J o u r n a l P r e -p r o o f Propofol Propofol overdose can trigger NLRP3 inflammasome activation via mitochondrial ROS-dependent pathway [110] Morphine Morphine by binding to TLR4 activates NF-κB and induce the secretion of NLRP3 [111] Imiquimod is a small-molecule ligand of TLR7 that is licensed for the treatment of viral infections and cancers of the skin.

Amodiaquine is a medication used to treat malaria. Nevirapine is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. Propofol (Diprivan), is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Morphine is a pain medication of the opiate family.

It should be noted excessive activation of the NLRP3 inflammasome may cause various diseases, including metabolic syndrome, cardiovascular and neurodegenerative diseases, diabetes, or atherosclerosis. Therefore, more and more specific scientific experiments occur in the literature concerning the discovery of potential inhibitors of inflammasomes with the goal of using them in the future as specific targets for inflammasome regulation and inflammation control.

Obovatol is a biphenolic natural chemical compound isolated from Magnolia obovata that has anti-inflammatory and neurotrophic properties. Numerous research shows that obovatol has anti-inflammasome properties and may be used for the treatment of Alzheimer's disease (AD), various types of cancer and atherosclerosis. For example, in AD model mice obovatol administration suppresses inflammation in microglial cells and improves cognitive function in animals [112] . It has been reported that obovatol may inhibit cancer cells proliferation via the inhibition of NF-kB signal transduction and apoptosis increase [113] . Moreover, by inhibiting the expression of cyclins and cyclin-dependent kinases obovatol reduces the number of vascular smooth muscle cells [114] . Also, in in vitro experiments on mouse bone marrow-derived macrophages and in vivo studies on mice, obovatol was found to inhibit NLRP3, AIM2, and non-canonical inflammasome expression. Obovatol affects the priming step of inflammasome activation and suppresses transcription of pro-inflammatory cytokine synthesis. Additionally, the inhibitory mechanism of obovatol relies on inhibition of mitochondrial ROS generation and Asc pyroptosome formation [115] . inflammasomes have been observed that support the role of MUC1 in the regulation of NLRP3 activation by bacteria [116] .

Catechin is a flavan-3-ol, a type of natural phenol, and has antioxidant properties. Catechin is present in many dietary products, green tea, red wine, beer, chocolate, and cocoa, among others, and possesses a range of beneficial health effects. There is evidence that emphasizes the protective effects of catechin against periodontitis and gouty inflammation. Such, in mice suffering from periodontitis induced by Porphyromonas gingivalis, downregulation of NLRP3 and AIM2 inflammasome activation was observed. Catechin also suppresses the production of IL-1β by inhibiting pro-IL-1β expression via the downregulation of nuclear factor-κB, p38 mitogen-activated protein kinase, and TLR signaling in THP-1 cells [117] . Similarly, subcutaneous injection of catechin decreases monosodium urate (MSU)-induced IL-1β and IL-6 secretion in C57BL/6 mice (in vivo) and inhibits MSU-induced IL-1β secretion, intracellular calcium and NLRP3 inflammasome activation in MSU-challenged THP-1 cells (in vitro) [118] .

These data suggest that catechin has anti-inflammatory properties by reducing inflammasome activity and pro-inflammatory cytokine synthesis in periodontitis and gout attack.

Dicer or helicase with RNase motif is a ribonuclease from the RNase III family (RNase III) that cleaves double-stranded RNA and pre-miRNA molecules to produce short double-stranded RNA fragments called small interfering RNAs (siRNAs) and microRNAs (miRNAs). Dicer promotes activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. In the experiment on the mouse suffering from retinal pathologies, genetic suppression of Dicer1 leads to focal retinal pigmented epithelium atrophy and aberrant retinal neovascularization in the eye [119] . In addition, dicer-deficient murine bone marrow macrophages show disturbances in NLRP3 inflammasome activation. Dicer is required for optimal secretion of mature IL-1β and caspase-1 following stimulation of the NLRP3 but not the AIM2 inflammasome. These data indicate that miRNAs are necessary for the production of mature micro-RNAs and NLRP3 inflammasome activation in bone marrow macrophages and underline key function of DICER1 in maintaining retinal homeostasis [119, 120] .

Heat-killed probiotics. It has been previously demonstrated that heat-killed probiotics can be useful for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis in mice. Treatment mice suffering from dextran sodium sulfate (DSS)-induced J o u r n a l P r e -p r o o f colitis with heat-killed E. faecalis amelioration of the severity of intestinal inflammation and the formation of colorectal cancer were observed. In contrast, E. faecalis cannot prevent DSSinduced colitis in NLRP3 knockout mice [68] . Moreover, in an experiment where THP-1derived macrophages were incubated with heat-killed E. faecalis commensal bacteria, a reduction of NLRP3 and caspase-1 activation and IL-1β maturation was observed. Above mentioned data suggesting that application of heat-killed probiotic, E. faecalis could be useful for attenuation of NLRP3-mediated inflammation in the gut and may prevent colon carcinogenesis [68] .

is an essential micronutrient that is necessary for proper antioxidant defense, reproduction, cancer prevention, immunity and health [121] . Several studies have demonstrated, that selenium by inhibition of the NLRP3 inflammasome activity attenuates Staphylococcus aureus mastitis and has an anti-inflammatory property in the mammary gland [122, 123] . In a mouse model of Staphylococcus aureus-induced mastitis selenium administration in the diet was found to suppress NALP3 inflammasome expression and inhibit the maturation of caspase-1 and IL-1β in mammary tissue. Selenium decreases the production of IL-1β by inhibiting activation of the NF-κB/p65 signaling pathway induced by Staphylococcus aureus, and downregulation of the NALP3 inflammasome and ASC expression participates in inflammation reduction [122, 123] Quercetin is the natural biochemical substance of the flavonoid group isolated from foods of plant origin. Quercetin is used in alternative medicine and is part of several biologically active [125] .

(an evergreen rainforest tree of the myrtle family Myrtaceae). Oridonin is widely used in J o u r n a l P r e -p r o o f traditional Chinese medicine and possesses anti-inflammatory and anticancer activity. Several data are showed that in an NLRP3 inflammasome-dependent manner oridonin exerts therapeutic effects on myocardial ischemia, liver fibrosis, neuroinflammation, colitis and sepsis. Also, there are reports that oridonin reduces lung inflammation and improves survival in SARS-CoV-infected animals [127] [128] [129] [130] [131] . The mechanism of oridonin action is based on the suppression of NF-κB or MAPK activity and inhibition of inflammasome-independent proinflammatory cytokines releases, such as TNF-α and IL-6 [132] . He et al. [133] in in vitro and in vivo experiments, demonstrated that oridonin is a covalent drug that can block NLRP3 inflammasome activation. They found that oridonin could form a covalent bond with cysteine 279 of NLRP3 in the NACHT domain to block the interaction between NLRP3 and NEK7, leading to inhibition of NLRP3 inflammasome assembly and downregulation of the expression of pro-inflammatory cytokines. [133] . This data suggest that oridonin could be used as a novel therapeutic against NLRP3-driven inflammation.

Based on literature data, the host activates the mechanism of inflammasomes formation as a defense response against the described pathogenic microorganisms, but in turn, some pathogens entering the organism using virulence factors may antagonize inflammasome pathways and increase their ability to survive in the host and cause disease. The host organism sometimes expresses excessive amounts of inflammasomes to remove harmful factors, which leads to the overproduction of inflammatory cytokines and can cause chronic inflammation and even autoinflammatory disease. Of note, probiotic bacteria do not impact inflammasome activation and pro-inflammatory cytokine synthesis in healthy individuals, but probiotics may regulate inflammasome activation in an organism that has previously experienced some degree of inflammation due to infection by pathogenic bacteria. Finally, by examining the signalling pathways responsible for the regulation of inflammasome activity, many biochemical substances have been discovered that have an inhibitory effect on inflammasome activity.

Knowledge about the mechanisms responsible for the interactions between the host and certain types of microorganisms could contribute to the individuation of innovative strategies for the treatment of autoinflammatory diseases targeting a specific type of inflammasome activated by specific type of pathogen.

J o u r n a l P r e -p r o o f . Pathogenic components and endogenous cytokines trigger NLRP3 inflammasome activation. Active NLRP3 inflammasome initiate activation caspase-1, which causes the transformation of pro-IL-1β and pro-IL-18 cytokines into IL-1 β and IL-18. Caspase-1 can also cleave gasdermin D protein, initiating cell death termed as pyroptosis. Fig. 2 . The scheme of NLRP3 inflammasome activation. For NLRP3 inflammasome formation, two signals are needed. The sources of the first signal are microbial components and endogenous cytokines (PAMPs or DAMPs). Here, the ligands of the Toll-like receptor (e.g., LPS) activates NFκB, leading to the expression of NLRP3 protein and upregulation of pro-IL-1β and pro-IL-18 synthesis. The second signal is transmitted, for example, by extracellular ATP molecules (1), reactive oxygen species (ROS) generation (2) or environmental irritants form intracellular crystalline (3). These agents activate the NLRP3 expression to first cause NLRP3 protein oligomerization and then ASC oligomerization, leading to the formation of the NLRP3 inflammasome. Inside the formed NLRP3 inflammasome, autoproteolysis of pro-caspase-1 leads to the creation of an active caspase-1, which in turn cleaves pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. J o u r n a l P r e -p r o o f

The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta

Inflammasomes: mechanism of action, role in disease, and therapeutics

Pyroptosis: The missing puzzle among innate and adaptive immunity crosstalk

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation

An update on autoinflammatory diseases

Interleukin-1 β Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study

Photoperiodic conditions as a factor modulating leptin influenceon pro-inflammatory cytokinesand their receptors gene expression in ewe's aorta

Pharmacological Inhibitors of the NLRP3 Inflammasome

HIV-1 induces the first signal to activate the NLRP3 inflammasome in monocyte-derived macrophages

Role of the inflammasomes in HIV-associated neuroinflammation and neurocognitive disorders

Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review

Modulation of inflammasome pathways by bacterial and viral pathogens

The pathology of influenza virus infections

Viroporins and inflammasomes: A key to understand virus-induced inflammation

Influenza virus activates inflammasomes via its intracellular M2 ion channel

Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation

Interplays between Enterovirus A71 and the innate immune system

Reciprocal Regulation between Enterovirus 71 and the NLRP3 Inflammasome

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

AIM2 Inflammasome-Mediated Pyroptosis in Enterovirus A71-Infected Neuronal Cells Restricts Viral Replication, Sci Rep

Role of SUMOylation in Human Oncogenic Herpesvirus Infection

A promiscuous inflammasome sparks replication of a common tumor virus

Epstein-Barr virus infectioninduced inflammasome activation in human monocytes

Characterization of viral proteins encoded by the SARS-coronavirus genome

Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A Potential Drug Target in the Treatment of COVID-19

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

The receptor binding domain of MERS-CoV: The dawn of vaccine and treatment development

Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-Converting Enzyme 2 as a Potential Drug Target -A Perspective

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells

COVID-19): A literature review

Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts

Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19

Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome

Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC

SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells

Inflammasome activation and regulation during Helicobacter pylori pathogenesis

Mechanisms of Inflammasome Signaling, microRNA Induction and Resolution of Inflammation by Helicobacter pylori

NLRP3 Activation Was Regulated by DNA Methylation Modification during Mycobacterium tuberculosis Infection

Genetic and pharmacological inhibition of inflammasomes reduces the survival of Mycobacterium tuberculosis strains in macrophages

Salmonella enterica: survival, colonization, and virulence differences among serovars

Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis

Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges

Regulatory Evolution Drives Evasion of Host Inflammasomes by Salmonella Typhimurium

Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression

Environmental Escherichia coli: ecology and public health implications-a review

Modulation of the Inflammasome Signaling Pathway by Enteropathogenic and Enterohemorrhagic Escherichia coli

Involvement of NLRP3 and NLRC4 Inflammasome in Uropathogenic E. coli Mediated Urinary Tract Infections

Activation of the NLRP3 Inflammasome Pathway by Uropathogenic Escherichia coli Is Virulence Factor-Dependent and Influences Colonization of Bladder Epithelial Cells

The relationship between caspase-1 related inflammasome expression and serum inflammatory cytokine levels during acute brucellosis

Critical Role of ASC Inflammasomes and Bacterial Type IV Secretion System in Caspase-1 Activation and Host Innate Resistance to Brucella abortus Infection

IL-1R and Inflammasomes Mediate Early Pulmonary Protective Mechanisms in Respiratory Brucella Abortus Infection

A visual review of the human pathogen Streptococcus pneumoniae

Syk and JNK signaling pathways are involved in inflammasome activation in macrophages infected with Streptococcus pneumoniae

NLRP3 inflammasome activation from Kupffer cells is involved in liver fibrosis of Schistosoma japonicum-infected mice via NF-κB

A Network of Physiological Interactions Modulating GI Homeostasis: Probiotics, Inflammasome, mTOR

Characterization of Inflammasome Components in Pig Intestine and Analysis of the Influence of Probiotic Enterococcus Faecium during an Escherichia Coli Challenge

Effects of a pathogenic ETEC strain and a probiotic Enterococcus faecium strain on the inflammasome response in porcine dendritic cells

Effects of ex-vivo and in-vivo treatment with probiotics on the inflammasome in dogs with chronic enteropathy

Pretreatment with a Heat-Killed Probiotic Modulates the NLRP3 Inflammasome and Attenuates Colitis-Associated Colorectal Cancer in Mice

Lactobacillus rhamnosus GR-1 Ameliorates Escherichia coli-Induced Inflammation and Cell Damage via Attenuation of ASC-Independent NLRP3 Inflammasome Activation

Nonpathogenic Lactobacillus rhamnosus activates the inflammasome and antiviral responses in human macrophages

Immunobiotic Lactobacillus strains augment NLRP3 expression in newborn and adult porcine gut-associated lymphoid tissues

Probiotic Escherichia coli Nissle 1917 and commensal E. coli K12 differentially affect the inflammasome in intestinal epithelial cells

Innate Defense against Fungal Pathogens, Cold Spring Harbor Perspectives in Medicine

Malassezia yeasts activate the NLRP3 inflammasome in antigen-presenting cells via Syk-kinase signalling

Pathogenic fungus Microsporum canis activates the NLRP3 inflammasome

NLRP3 inflammasome is a key player in human vulvovaginal disease caused by Candida albicans

A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans

Aspergillus Biofilms in Human Disease

Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection

Paracoccidioides brasiliensis AND Paracoccidioides lutzii, A SECRET LOVE AFFAIR

Enhanced expression of NLRP3 inflammasome components by monocytes of patients with pulmonary paracoccidioidomycosis is associated with smoking and intracellular hypoxemia

NLRP3 inflammasome is involved in the recognition of Paracoccidioides brasiliensis by human dendritic cells and in the induction of Th17 cells

Inflammasomes in host response to protozoan parasites

Inflammasome activation restrains the intracellular Neospora caninum proliferation in bovine macrophages

NLRP3 Inflammasome Participates in Host Response to Neospora caninum Infection

Leishmania donovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2

Leishmania infantum infection reduces the amyloid β42-stimulated NLRP3 inflammasome activation

AIM2 inflammasome is associated with disease severity in tegumentary leishmaniasis caused by Leishmania (V.) braziliensis

Schistosoma comparative genomics: integrating genome structure, parasite biology and anthelmintic discovery

Activation of the NLRP3 and AIM2 inflammasomes in a mouse model of Schistosoma mansoni infection

Immune responses against protozoan parasites: a focus on the emerging role of Nod-like receptors

The NLRP3 Inflammasome Is a Pathogen Sensor for Invasive Entamoeba histolytica via Activation of α5β1 Integrin at the Macrophage-Amebae Intercellular Junction

Inflammasomes: mechanism of assembly, regulation and signalling

Activation and regulation of the inflammasomes

HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation

ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

Type I interferon inhibits interleukin-1 production and inflammasome activation

Emerging Activators and Regulators of Inflammasomes and Pyroptosis

Cathepsin B Affects the Activation of Nucleotide-binding Domain and Leucine-rich-repeat-containing Family and Pyrin Domaincontaining 3 Inflammasome via Transient Receptor Potential Mucolipin-1], Zhongguo Yi Xue Ke Xue Yuan Xue Bao

Gout-associated uric acid crystals activate the NALP3 inflammasome

NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

Exogenous nanoparticles and endogenous crystalline molecules as danger signals for the NLRP3 inflammasomes

Inflammasomes in neuroinflammatory and neurodegenerative diseases

Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system

Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica

The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes

Critical Role for NALP3/CIAS1/Cryopyrin in Innate and Adaptive Immunity through Its Regulation of Caspase-1

Inflammasome Activation by Small Molecules Targeting Mitochondria

Supernatant from Hepatocyte Cultures with Drugs That Cause Idiosyncratic Liver Injury Activates Macrophage Inflammasomes

Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

Obovatol attenuates microglia-mediated neuroinflammation by modulating redox regulation: Microglial inhibition by obovatol

Inflammasomes in cancer: a doubleedged sword

Therapeutic applications of compounds in the Magnolia family

Obovatol inhibits NLRP3, AIM2, and non-canonical inflammasome activation

The MUC1 mucin specifically inhibits activation of the NLRP3 inflammasome

Catechin ameliorates Porphyromonas gingivalis-induced inflammation via the regulation of TLR2/4 and inflammasome signaling

Protective Effects of Catechin against Monosodium Urate-Induced Inflammation through the Modulation of NLRP3 Inflammasome Activation

Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice

Dicer regulates activation of the NLRP3 inflammasome

Effect of dietary organic selenium (Se) on immune response, hepatic antioxidant status, selenoprotein gene expression and meat oxidative stability in lambs

Selenium Attenuates Staphylococcus aureus Mastitis in Mice by Inhibiting the Activation of the NALP3 Inflammasome and NF-κB/MAPK Pathway

Selenium Plays an Anti-Inflammatory Role by Regulation NLRP3 Inflammasome in Staphylococcus aureus-Infected Mouse Mammary Gland

Role of Quercetin Benefits in Neurodegeneration

Quercetin Inhibits Inflammasome Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis

Quercetin suppresses NLRP3 inflammasome activation in epithelial cells triggered by Escherichia coli O157:H7, Free Radic

Oridonin's therapeutic effect: Suppressing Th1/Th17 simultaneously in a mouse model of Crohn's disease: Oridonin modulates CD4 + cells in colitis

Oridonin Attenuates Aβ1-42-Induced Neuroinflammation and Inhibits NF-κB Pathway

Oridonin Attenuates Myocardial Ischemia/Reperfusion Injury via Downregulating Oxidative Stress and NLRP3 Inflammasome Pathway in Mice, Evidence-Based Complementary and Alternative Medicine

Oridonin ameliorates carbon tetrachloride-induced liver fibrosis in mice through inhibition of the NLRP3 inflammasome

Inhibition of NF-B-Mediated Inflammation in Severe Acute Respiratory Syndrome Coronavirus-Infected Mice Increases Survival

Oridonin attenuates the release of pro-inflammatory cytokines in lipopolysaccharide-induced RAW264.7 cells and acute lung injury

Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity

Fig.1. NLRP3 inflammasome composition. The NLRP3 inflammasome consists of domains: LRR (leucine-rich repeat domain), NAD (binding domain), NACHT(nucleotide-binding and oligomerization domain

CARD (caspase recruitment domain)

Pathogenic components and endogenous cytokines trigger NLRP3 inflammasome activation

Active NLRP3 inflammasome initiate activation caspase-1, which causes the transformation of pro-IL-1β and pro-IL-18 cytokines into IL-1 β and IL-18. Caspase-1 can also cleave gasdermin D protein

LPS) activates NFκB, leading to the expression of NLRP3 protein and upregulation of pro-IL-1β and pro-IL-18 synthesis. The second signal is transmitted, for example, by extracellular ATP molecules (1), reactive oxygen species (ROS) generation (2) or environmental irritants form intracellular crystalline (3). These agents activate the NLRP3 expression to first cause NLRP3 protein oligomerization and then ASC oligomerization, leading to the formation of the NLRP3 inflammasome. Inside the formed NLRP3 inflammasome, autoproteolysis of pro-caspase-1 leads to the creation of an active caspase-1

During AIM2 inflammasome activation, the AIM2 protein functions as an initiating component that recognizes the cytoplasmically located dsDNA (DNA-binding HIN-200 domain), whereas the ASC protein functions as the pro-caspase-1 activator and caspase-1 as an effector component

Active AIM2 inflammasome initiate activation caspase-1, which causes the transformation of pro-IL-1β and pro-IL-18 cytokines into IL-1 β and IL-18 and induction of pyroptosis

None declared.