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Alzheimer’s disease (AD) is the most common cause of dementia in the general population and, to date, constitutes a major therapeutic challenge. In the pathogenesis of AD, aggregates of amyloid β (Aβ) and neurofibrillary tangles (NFTs) containing Tau-microtubule-associated protein (tau) are known to trigger a neuroinflammatory response with subsequent formation of an inflammasome. In particular, the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is thought to play a crucial role in AD-related pathology. While the mechanisms for NLRP3 activation are not fully understood, it has been demonstrated that, after detection of protein aggregates, NLRP3 induces pro-inflammatory cytokines, such as interleukin 18 (IL-18) or interleukin 1β (IL-1β), that further potentiate AD progression. Specific inhibitors of NLRP3 that exhibit various mechanisms to attenuate the activity of NLRP3 have been tested in in vivo studies and have yielded promising results, as shown by the reduced level of tau and Aβ aggregates and diminished cognitive impairment. Herein, we would like to summarize the current state of knowledge on NLRP3 inflammasome priming, activation, and its actual role in AD pathogenesis, and to characterize the NLRP3 inhibitors that have been studied most and their impact on AD-related pathology.

Oral cancer is one of the most common human malignancies, and its incidence is increasing worldwide. In particular, oral squamous cell carcinoma (OSCC) is characterized by high rates of proliferation, invasiveness, and metastasis. Currently, standard treatment for OSCC includes surgical removal, chemotherapy, and radiotherapy; however, the survival rate of patients with OSCC remains low, thus new therapies are needed. It has been proven that excessive NLRP3 inflammasome activation and apoptosis alteration may contribute to oral cancer progression. This study aimed to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in an in vitro and in vivo xenograft model of oral cancer. In vitro results revealed that BAY-117082 at concentrations of 5, 10, and 30 µM was able to reduce OSCC cell viability. BAY-117082 at higher concentrations significantly reduced NLRP3, ASC, caspase-1, IL-1β, and IL-18 expression. Moreover, Bax, Bad, and p53 expression were increased, whereas Bcl-2 expression was reduced. Furthermore, the in vivo study demonstrated that BAY-117082 at doses of 2.5 and 5 mg/kg significantly decreased subcutaneous tumor mass, and also reduced NLRP3 inflammasome pathway activation. Therefore, based on these results, the use of BAY-117082 could be considered a promising strategy to counteract oral cancer progression, thanks its ability to modulate the NLRP3 inflammasome and apoptosis pathways.

Background Phagocyte NADPH oxidase 2 (NOX2) is an enzyme complex responsible for reactive oxygen species (ROS) production. Chronic NOX2 activity sustains oxidative stress/damage and drives neuroinflammation following traumatic brain injury (TBI). NOX2 acts as a priming signal for NLRP3 inflammasome activation, which also plays a role in secondary injury after TBI. GSK2795039 is a small molecule brain penetrable drug that inhibits NOX2 in a NADPH competitive manner. Here, we investigated whether pharmacological inhibition of NOX2 using GSK2795039 can reduce secondary neuroinflammation after TBI, specifically via inhibition of downstream NLRP3 inflammasome activation, in both resident microglia and infiltrating myeloid cells in the injured brain. Methods Immortalised microglial (IMG) cells or primary microglia were pre-treated with GSK2795039 (NOX2 inhibitor) or MCC950 (NLRP3 inhibitor) and stimulated with lipopolysaccharide and nigericin to induce NOX2/ROS and NLRP3 inflammasome activation. The controlled cortical impact model, pharmacokinetic analyses, multi-dimensional flow cytometry, histology and neurobehavioral assessments were used to translate in vitro findings to an experimental TBI model in adult male C57BL6/J mice. Results The small molecule NOX2 inhibitor, GSK2795039, attenuated microglial NOX2 activity, thereby reducing ROS, nitrite and cytokine levels, as well as NLRP3 inflammasome components in pro-inflammatory microglia. TBI recruited NOX2/ROS/IL-1β + neutrophils and inflammatory monocytes into injured brain parenchyma with peak monocytic NOX2/ROS/IL-1β production at 3 days post-injury (DPI), coincident with peak NOX2/ROS/IL-1β expression in microglia. Systemic administration of GSK2795039 (100 mg/kg; I.P.) starting 2 h post-injury attenuated NOX2/IL-1β + microglial and infiltrating myeloid cell activation at 3 days post-injury. In addition, NOX2 inhibition reduced numbers of IL-1R + T cells in the brain of TBI mice, indicating that myeloid-T cell crosstalk was altered by GSK2795039 treatment. Innate and adaptive neuroimmune changes were associated with improvements in motor function post-TBI. In the chronic phase through 28 days post-injury, pharmacological inhibition of NOX2 by GSK2795039 treatment resulted in modest improvements in neurobehavioral deficits and TBI neuropathology. Conclusions These pre-clinical studies identify the NOX2-ROS-NLRP3 inflammasome axis along with myeloid-T cell crosstalk as effective targets for TBI neuroinflammation. Our translational studies indicate that NOX2 may be a promising therapeutic target for mitigating neuroinflammation in microglia, and peripheral immune cells, following experimental TBI in mice.

Cancer-induced bone pain (CIBP) is characterized as moderate to severe pain that negatively affects the daily functional status and quality of life of patients. When cancer cells metastasize and grow in bone marrow, this activates neuroinflammation in the spinal cord, which plays a vital role in the generation and persistence of chronic pain. In the present study, a model of CIBP was constructed by inoculating of MRMT-1 rat breast carcinoma cells into the medullary cavity of the tibia in male Sprague-Dawley rats. Following two weeks of surgery, CIBP rats exhibited damaged bone structure, increased pain sensitivity and impaired motor coordination. Neuroinflammation was activated in the spinal cords of CIBP rats, presenting with extensive leukocyte filtration, upregulated cytokine levels and activated astrocytes. Histone deacetylase 6 (HDAC6) works as a therapeutic target for chronic pain. The intrathecal injection of the HDAC6 inhibitor tubastatin A (TSA) in the lumbar spinal cord resulted in decreased spinal inflammatory cytokine production, suppressed spinal astrocytes activation and reduced NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activity. Consequently, this effect alleviated spontaneous pain and mechanical hyperalgesia and recovered motor coordination in CIBP rats. It was demonstrated by immunoprecipitation assay that TSA treatment reduced the interaction between HDAC6 and NLRP3. Cell research on C6 rat glioma cells served to verify that TSA treatment reduced HDAC6 and NLRP3 expression. In summary, the findings of present study indicated that TSA treatment alleviated cancer-induced bone pain through the inhibition of HDAC6/NLRP3 inflammasome signaling in the spinal cord.

Spiraea prunifolia : var. simpliciflora (SP) is a known medical food that is used to treat emesis, malaria, and fever. This study investigated the therapeutic potential of SP leaf extract on oxidative stress and airway inflammation using a chronic obstructive pulmonary disease (COPD) mouse model induced by porcine pancreatic elastase (PPE) and lipopolysaccharide (LPS). Male C57BL/6N mice were treated intratracheal instillation of PPE (0.05 units/50 μL) and LPS (5 μg/50 μL), and administered positive control (dexamethasone; 3 mg/kg) and SP (50 and 100 mg/kg). SP treatment decreased T helper type 1 (Th-1) cytokines as well as counts of macrophage and neutrophil in bronchoalveolar lavage fluid of PPE/LPS-induced COPD. SP treatment reduced alveolar destruction, inflammatory cell infiltration, and collagen fiber with improvement of forced expiratory volume to forced vital capacity ratio and lung elastance in lung tissue. SP downregulated thioredoxin-interacting protein and NOD-like receptor pyrin domain-containing 3 inflammasome which inhibited caspase-1 and IL-1β expression. SP attenuated production of reactive oxygen and nitric oxide through enhancement of nuclear factor-erythroid 2-related factor translocation with elevation of heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1 expression. Furthermore, SP attenuated the levels of reactive oxygen species and nitric oxide in mice with PPE/LPS-induced COPD. Thus, SP has the therapeutic potential for COPD treatment.

Parkinson’s disease (PD) is characterized by progressive neurodegeneration closely linked to neuroinflammation and oxidative stress-induced damage and is characterized by the loss of dopaminergic (DAergic) neurons and the inflammatory response associated with glial cells. RRx-001 (RRx, 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone) is a small-molecule immunoregulator. Recent studies have shown that it strongly inhibits NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, which is crucial for influencing neuroinflammation. However, the mechanism underlying the effect of RRx on PD remains unclear. In this study, we explored the potential effects of RRX on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, detected the transcriptome and metabolome of the substantia nigra, and performed 16 S microbial diversity sequencing and metabolomics of the intestinal tract. Our study revealed that RRx obviously relieves MPTP-induced DAergic neuronal loss and motor disorders. Mechanistically, RRx reversed the upregulated expression of lipocalin-2 (LCN2) and NLRP3 inflammasome activation in a PD model. Crucially, its protective effects on DAergic neurons involved improving LCN2-NLRP3 inflammasome activation-mediated astrocyte pyroptosis. RRx also reduced the levels of metabolites and signalling pathways associated with oxidative stress and PD in the substantia nigra. Furthermore, the 16 S rDNA analysis and metabolomic analysis of faecal pellets revealed that the intestinal tract of the RRx-treated PD mice presented a greater abundance of Deferribacterota at the phylum level than that of the PD model mice, and the gut microbiota metabolites and pathways were altered. Overall, the results of this study indicate that RRx has multiple effects on PD.

Trigeminal neuralgia (TN) is characterized by neuroinflammation and satellite glial cell (SGC) activation, but the molecular mechanisms remain unclear. This study identifies zinc finger MIZ-type containing 1 (Zmiz1) as a key regulator that promotes SUMOylation of NLRP3 inflammasome, thereby influencing SGC activation and neuronal autophagy in TN. Using bioinformatics analysis, we identified Zmiz1 as a key SUMOylation-related gene involved in TN. Single-cell transcriptomics and co-expression network analysis revealed Zmiz1 enrichment in SGCs and neurons. Co-immunoprecipitation (Co-IP) and western blotting confirmed Zmiz1’s interaction with NLRP3 and its role in promoting NLRP3 SUMOylation. In vitro experiments assessed the impact of Zmiz1 overexpression and knockdown on SGC activation, inflammatory cytokine secretion, and neuronal autophagy. A TN rat model was established to evaluate pain behavior, neuroinflammation, and neuronal apoptosis. Zmiz1 overexpression significantly enhanced NLRP3 SUMOylation, promoting SGC activation and inflammation while inhibiting neuronal autophagy. Conversely, silencing Zmiz1 reduced neuroinflammation and improved neuronal viability. In vivo, Zmiz1 knockdown alleviated TN-associated pain hypersensitivity and neuronal apoptosis. This study unveils a novel mechanism by which Zmiz1 regulates TN via NLRP3 SUMOylation, highlighting the Zmiz1/NLRP3 axis as a potential therapeutic target for TN treatment.

Background and Aim: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1β (IL-1β) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis. Methods: Small intestinal mucositis was induced in wild-type, NLRP3 –/– , and caspase-1 –/– mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1β or IL-18, or neutralizing antibody against IL-1β. Results: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1β and protein expression of cleaved caspase-1 and mature IL-1β. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3 –/– mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1β and neutralized by IL-1β antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1β were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells. Conclusions: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1β maturation.

Luteolin (LO) possesses pharmacological benefits like anti-inflammatory, antioxidant, and immune-boosting properties. This study aims to clarify the effect of LO on allergic rhinitis (AR) and its mechanisms and provide new insights for the clinical application of LO. A mouse model for AR was developed through ovalbumin (OVA) stimulation. AR mice were gavaged with saline, low, medium, and high concentrations of LO, and montelukast. Nasal symptoms and scores were evaluated. The levels of OVA-specific immunoglobulins (OVA-sIgs), T helper cells (Th1, Th2, Th17), regulatory T cells (Tregs) cytokines, along with proinflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Histopathological alterations were observed utilizing hematoxylin-eosin staining. Interleukin (IL)-1β and IL-18 levels were assessed through immunohistochemistry. Flow cytometry measured the percentage of T lymphocytes. The levels of endoplasmic reticulum stress (ERS)-related and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related mRNAs and proteins were analyzed through reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. LO reduced nasal symptom scores in AR mice, upregulated OVE-sIgG2a levels, and downregulated OVE-sIgE, OVE-sIgG1, and histamine levels. After the administration of LO, AR mice showed an increase in Th1 and Treg cytokines levels, while Th2 and Th17 cytokines levels were reduced. LO ameliorated the splenic T cell subset imbalance and attenuated inflammatory cell infiltration. LO reduced the levels of ERS-related and NLRP3 inflammasome activation-related mRNAs and proteins in the nasal mucosa. LO ameliorated AR symptoms by regulating T cell subset imbalance, hindering ERS and NLRP3 inflammasome activation.

AbstractOne type of age-related macular degeneration (AMD), neovascular (nAMD), characterized by choroidal neovascularization (CNV), accounts for the majority of the severe central vision impairment associated with AMD. Endothelial cells (ECs) in direct contact with retinal pigment epithelial (RPE) cells are more prone to the pathological angiogenesis involved in CNV. Herein, we investigated the effect of crosstalk between RPE cells and choroidal endothelial cells (CECs) via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis on the development of choroidal neovascularization (CNV) in vitro and in vivo. ANXA1 expression and secretion from ARPE-19 cells were upregulated by hypoxia. FPR2 expression, especially on the plasma membrane, in HCECs was upregulated under hypoxic conditions. ANXA1 secreted from ARPE-19 cells inhibited NLRP3 inflammasome activation and NLRP3 inflammasome-mediated pyroptosis in HCECs by activating the FPR2/SHP2 axis. Moreover, ANXA1 secreted by ARPE-19 cells promoted behaviors of HCECs, including proliferation, migration, and tube formation, by activating the FPR2/SHP2 axis and inhibiting NLRP3 inflammasome-mediated pyroptosis. Inhibiting the upregulated ANXA1/FPR2/SHP2/NLRP3 inflammasome/pyroptosis axis decreased the volume of CNV. Our data suggest that the crosstalk between RPE cells and CECs via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis promotes CNV. This finding could identify a potential target for the prevention and treatment of CNV.