Targeting NLRP3 Research Articles

Inhibition of NLRP3 inflammasome contributes to paclitaxel efficacy in triple negative breast cancer treatment.

Chronic inflammation and NLRP3 inflammasome activation are among the determining factors of breast malignancies. Paclitaxel (PTX) is a drug used in breast cancer treatment which sustains prolonged inflammation, reducing the effectiveness of chemotherapy. Considering the impact of inflammatory processes in cancer progression, there is a strong concern to develop therapeutic strategy targeting NLRP3 inflammasome for triple-negative breast cancer (TNBC) treatment. Therefore, the aim of this study was to evaluate the potential of PTX and NLRP3 inflammasome modulation to counterbalance TNBC by inducing programmed cell death and inhibiting the activity of pro-inflammatory cytokines. The obtained results suggested the strong interaction between NLRP3 inflammasome and TNBC and revealed that pharmacological inhibition, using NLRP3-specific inhibitor MCC950, and genetic silencing of NLRP3 inflammasome using specific small interfering RNA, reduced inflammatory responses and facilitated PTX-determined tumor cell death. Thus, NLRP3 inflammasome manipulation in combination with anti-tumor drugs opens up new therapeutic perspectives for TNBC therapy.

Glibenclamide Prevents Inflammation by Targeting NLRP3 Inflammasome Activation In Vitro

The NLRP3 inflammasome is known to play a significant role in the development of neurodegeneration and physiological aging, as well as the development of metabolic inflammation, which has generated significant interest in the scientific community in finding effective inhibitors of the NLRP3 inflammasome and assessing their effects. The purpose of this study was to evaluate the effect of pharmacological modulation of NLRP3 activity using an indirect NLRP3 inflammasome inhibitor, glibenclamide, on the expression of metaflammasome components in in vitro brain cells obtained from middle-aged mice. The study revealed that glibenclamide reduces the expression of pro-inflammatory markers NLRP3 and IL18 in cell culture, which in turn leads to the prevention of phosphorylation of protein kinases of the metaflammasome complex – PKR and IKKβ. However, we did not observe changes in the expression of pathologically phosphorylated IRS, as well as in the number of senescent cells in cultures after the exposure to glibenclamide.

Scaffold hopping-driven optimization for the identification of NLRP3 inhibitors as potential gout therapeutics

Gout as a common inflammatory arthritis seriously affects the quality of life of a large number of people. Targeting NLRP3 inflammasome has been certified as a promising therapeutic strategy for gout. This study, a series of new imidazolidinone derivatives were validated as NLRP3 inhibitors by scaffold hopping from the reported NLRP3 inhibitor CSC-6. In contrast to the poor physicochemical properties of the template molecule, the representative compound 23 showed good plasma stability, water solubility, and no significant inhibitory toxicity to CYP450 enzymes. Surface plasmon resonance and immunoblotting experiments showed that compound 23 binds NLRP3 and inhibits NLRP3 activation. Finally, compound 23 showed good anti-inflammatory and analgesic effects in acute peritonitis and arthritis. Overall, the present study provides NLRP3 inhibitors with favorable pharmacological properties, which may not only serve as a tool molecule for studying NLRP3-related functions, but also may further facilitate the gout treatment.

Targeting NLRP3 inhibits AML progression by inducing PERK/eIF2-mediated apoptosis

BackgroundAcute myeloid leukemia (AML) is characterized by the abnormal proliferation of myeloid precursor cells and presents significant challenges in treatment due to its heterogeneity. Recently, the NLRP3 inflammasome has emerged as a potential contributor to AML pathogenesis, although its precise mechanisms remain poorly understood.MethodsPublic genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1β, IL-18, ASC, and NLRP3) in AML patients compared to healthy individuals. CRISPR/Cas9 technology was employed to generate NLRP3-deficient MOLM-13 AML cells, followed by comprehensive characterization using real-time PCR, western blotting, FACS analysis, and transmission electron and immunofluorescence microscopy. Proteomic analyses were conducted to identify NLRP3-dependent alterations in protein levels, with a focus on the eIF2 kinase PERK-mediated signaling pathways. Additionally, in vivo studies were performed using a leukemic mouse model to elucidate the pathogenic role of NLRP3 in AML.ResultsElevated expression of NLRP3 was significantly associated with diminished overall survival in AML patients. Genetic deletion, pharmacological inhibition and silencing by RNA interference of NLRP3 led to decreased AML cell survival through the induction of apoptosis. Proteomic analyses uncovered NLRP3-dependent alterations in protein translation, characterized by enhanced eIF2α phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2α phosphorylation reduced apoptosis by downregulating pro-apoptotic Bcl-2 family members. In vivo studies demonstrated reduced leukemic burden in mice engrafted with NLRP3 knockout AML cells, as evidenced by alleviated leukemic symptoms.ConclusionOur findings elucidate the involvement of the NLRP3/PERK/eIF2 axis as a novel driver of AML cell survival. Targeting NLRP3-induced signaling pathways, particularly through the PERK/eIF2 axis, presents a promising therapeutic strategy for AML intervention. These insights into the role of the NLRP3 inflammasome offer potential avenues for improving the prognosis and treatment outcomes of AML patients.

Male Akita diabetic mice develop underactive bladder independent of NLRP3 that can be prevented with blood glucose control

Aim:Diabetic bladder dysfunction (DBD) is the most common diabetic complication. Patients present with overactive symptoms, underactive symptoms, or both. While strict glucose control may be expected to reverse DBD, prior studies have not been supportive. However, we hypothesize that strict control, soon after hyperglycemia appears, can prevent DBD development. Moreover, 50% of adult diabetics are poorly-controlled and it is unknown how this effects development of DBD. Thus, we investigated the effect of early glucose control (poor and strict) on DBD in male Akita diabetic mice (type 1). NLRP3-induced inflammation is critical to development of DBD in female Akita. Therefore, we also hypothesized that targeting NLRP3 may control or prevent DBD in male Akita, especially in a poorly-controlled population. Methods:Akita mice (±NLRP3) were stratified into uncontrolled, poorly-controlled and strictly-controlled diabetic groups using insulin treatment (0, 0.125 or 0.25 U/day). Mice were assessed at 15 weeks for blood glucose, HbA1c, Evans blue dye extravasation (a marker of capillary permeability/inflammation) and bladder function. Results:Blood glucose was elevated in diabetics, reduced in an insulin dose-dependent manner, and not affected by NLRP3 deletion. HbA1c levels followed a similar course but were more sensitive to insulin levels. Evans blue dye extravasation was prevented with glucose control and absent in NLRP3−/− mice. Diabetics exhibited signs of underactive bladder (increased void volume, decreased frequency) that was attenuated in the uncontrolled group but absent in the well-controlled group. Deleting NLRP3 did not affect voiding function. Conclusion:Male Akita mice develop an underactive-like bladder, independent of NLRP3, which can be prevented with glucose control.

Targeting NLRP3 Inflammasomes: A Trojan Horse Strategy for Intervention in Neurological Disorders.

Recently, a growing focus has been on identifying critical mechanisms in neurological diseases that trigger a cascade of events, making it easier to target them effectively. One such mechanism is the inflammasome, an essential component of the immune response system that plays a crucial role in disease progression. The NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome is a subcellular multiprotein complex that is widely expressed in the central nervous system (CNS) and can be activated by a variety of external and internal stimuli. When activated, the NLRP3 inflammasome triggers the production of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) and facilitates rapid cell death by assembling the inflammasome. These cytokines initiate inflammatory responses through various downstream signaling pathways, leading to damage to neurons. Therefore, the NLRP3 inflammasome is considered a significant contributor to the development of neuroinflammation. To counter the damage caused by NLRP3 inflammasome activation, researchers have investigated various interventions such as small molecules, antibodies, and cellular and gene therapy to regulate inflammasome activity. For instance, recent studies indicate that substances like micro-RNAs (e.g., miR-29c and mR-190) and drugs such as melatonin can reduce neuronal damage and suppress neuroinflammation through NLRP3. Furthermore, the transplantation of bone marrow mesenchymal stem cells resulted in a significant reduction in the levels of pyroptosis-related proteins NLRP3, caspase-1, IL-1β, and IL-18. However, it would benefit future research to have an in-depth review of the pharmacological and biological interventions targeting inflammasome activity. Therefore, our review of current evidence demonstrates that targeting NLRP3 inflammasomes could be a pivotal approach for intervention in neurological disorders.

3,5-Dimethyl-8-methoxy-3,4-dihydro-1H-isochromen-6-ol Attenuates Ulcerative Colitis via Targeting NLRP3 in Mice.

3,5-Dimethyl-8-methoxy-3,4-dihydro-1H-isochromen-6-ol (DMD) is a polyketide compound obtained from the endophytic fungus Penicillium sp. HJT-A-10 of Rhodiola tibetica. R. tibetica is a nourishing food and also used in traditional Chinese medicine and Xizang medicine. In dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice, DMD significantly alleviated the pathological symptom of UC. Network pharmacology studies have shown that nucleotide-binding domain-like receptor family pyrin domain containing (NLRP) 3 is the primary target protein of DMD associated with anti-UC. In molecular biology studies, DMD suppressed the activation of NLRP3 and decreased the expression of downstream inflammatory proteins and pro-inflammatory cytokines in UC. The finding was further verified in knockout mice. DMD lost the effect of attenuating DSS-induced UC in NLRP3-/- mice. In conclusion, this study demonstrates that DMD reduces inflammatory response and balances the barrier integrity to attenuate UC via targeting NLRP3, and DMD is a potential natural agent or dietary supplement for attenuating UC.

Paeonol attenuated high glucose-induced apoptosis via up-regulating miR-223-3p in mouse cardiac microvascular endothelial cells

To investigate the role of miR-223-3p in the modulatory effect of paeonol (Pae) on high glucose (HG)-induced endothelial cell apoptosis. HG (25 mmol/L) was used to induce cellular damage and apoptosis in the mouse cardiac microvascular endothelial cells (MCMECs). Various concentration of Pae was tested and 60 μmol/L Pae was selected for the subsequent studies. MCMECs were transfected with exogenous miR-223-3p mimics or anti-miR-223-3p inhibitors. Cell viability was assessed by MTT assay and apoptosis was quantified by flow cytometry. The expression of miR-223-3p and NLRP3 mRNA was measured using real-time quantitative RT-PCR, and protein level of NLRP3 and apoptosis-related proteins was detected by immunoblotting. Pae significantly attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. In addition, Pae (60 µmol/L) significantly reversed HG-induced down-regulation of miR-223-3p and up-regulation of NLRP3. Pae (60 µmol/L) also significantly blocked HG-induced up-regulation of Bax and Caspase-3 as well as down-regulation of Bcl-2. Moreover, exogenous miR-223-3p mimics not only significantly attenuated HG-induced apoptosis, but also significantly suppressed NRLP-3 and pro-apoptotic proteins in the MCMECs. In contrast, transfection of exogenous miR-223-3p inhibitors into the MCMECs resulted in not only significantly increased apoptosis of the cells, but also significant suppression of NLRP3 and pro-apoptotic proteins in the cells. Pae attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. MiR-223-3p may mediate the modulatory effects of Pae on MCMEC survival or apoptosis through targeting NLRP3 and regulating apoptosis-associated proteins.

Brusatol alleviates pancreatic carcinogenesis via targeting NLRP3 in transgenic Krastm4Tyj Trp53tm1Brn Tg (Pdx1-cre/Esr1*) #Dam mice

BackgroundPancreatic cancer (PanCa), ranked as the 4th leading cause of cancer-related death worldwide, exhibits an dismal 5-year survival rate of less than 5 %. Chronic pancreatitis (CP) is a known major risk factor for PanCa. Brusatol (BRT) possesses a wide range of biological functions, including the inhibition of PanCa proliferation. However, its efficacy in halting the progression from CP to pancreatic carcinogenesis remains unexplored. MethodsWe assess the effects of BRT against pancreatic carcinogenesis from CP using an experimentally induced CP model with cerulein, and further evaluate the therapeutic efficacy of BRT on PanCa by employing Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mouse model. ResultsOur finding demonstrated that BRT mitigated the severity of cerulein-induced pancreatitis, reduced pancreatic fibrosis and decreased the expression of α-smooth muscle actin (α-SMA), which is a biomarker for pancreatic fibrosis. In addition, BRT exerted effects against cerulein-induced pancreatitis via inactivation of NLRP3 inflammasome. Moreover, BRT significantly inhibited tumor growth and impeded cancer progression. ConclusionsThe observed effect of BRT on impeding pancreatic carcinogenesis through targeting NLRP3 inflammasome suggests its good potential as a potential agent for treatment of PanCa.

Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Targeting NLRP3 inflammasome, specifically its interaction with NEK7 via the LRR domain of NLRP3, is a promising therapeutic strategy. Our research aimed to disrupt this interaction by focusing on the LRR domain. Through virtual screening, we identified five compounds with potent anti-inflammatory effects and ideal LRR binding affinity. Lead compound C878-1943 underwent structural optimization, yielding pyridoimidazole derivatives with different anti-inflammatory activities. Compound I-19 from the initial series effectively inhibited caspase-1 and IL-1β release in an adjuvant-induced arthritis (AIA) rat model, significantly reducing joint swelling and spleen/thymus indices. To further enhance potency and extend in vivo half-life, a second series including II-8 was developed, demonstrating superior efficacy and longer half-life. Both I-19 and II-8 bind to the LRR domain, inhibiting NLRP3 inflammasome activation. These findings introduce novel small molecule inhibitors targeting the LRR domain of NLRP3 protein and disrupt NLRP3-NEK7 interaction, offering a novel approach for RA treatment.

Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity.

Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound 5 possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound 32 was obtained by optimization of 5, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound 32 showed enhanced safety index (SI) relative to oridonin (IC50 = 77.2 vs 780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome assembly and activation. Furthermore, diverse agonists-induced activations of NLRP3 could be impeded by compound 32 without altering NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed tolerable pharmaceutical properties and significant anti-inflammatory activity in MSU-induced gouty arthritis model. Therefore, this work enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential candidate for the treatment of NLRP3-associated diseases.

In vitro study of momordin Ic in improving atopic dermatitis by regulating claudin-1/MyD88 and targeting NLRP3

Atopic dermatitis (AD) is a non-infectious inflammatory skin disease characterized by persistent itching of the skin, and it has become a global health problem with increasing incidence and complex pathogenesis. Momordin Ic (MMI) is a triterpenoid saponin that has anti-inflammatory effect and may play an effective role in the treatment of AD. To explore the molecular mechanism of MMI in relieving AD, and to provide some experimental data for the clinical application of MMI in AD. The mRNA levels of IL-33, IL-4 and NF-κB were detected by RT-qPCR. The protein expressions of Filaggrin, Claudin-1, MyD88 and NLRP3 were detected by western blotting. Transepithelial/transendothelial electrical resistance (TEER) method was used to detect the tight-junction function of HaCaT cells. Molecular docking experiment was performed on CB-DOCK2 to predict the binding of MMI and NLRP3. MMI reversed the decrease of filaggrin protein expression and intercellular resistance in HaCaT cells induced by TNF-α and IFN-γ. In addition, MMI reversed the increase in IL-33 and IL-4 mRNA levels in HaCaT cells treated with TNF-α and IFN-γ. In addition, MMI promoted the expression of Claudin-1 and inhibited the expression of MyD88 and NLRP3. In addition, the molecular docking results showed that MMI and NLRP3 had interaction sites. MMI improved the inflammatory response of HaCaT cells by regulating the expression of Claudin-1/MyD88 and targeting NLRP3, which may act a positive role in relieving AD.

Inhibition of NLRP3 inflammasome by MCC950 under hypoxia alleviates photoreceptor apoptosis via inducing autophagy in Müller glia.

NLRP3 inflammasome activation has emerged as a critical initiator of inflammatory response in ischemic retinopathy. Here, we identified the effect of a potent, selective NLRP3 inhibitor, MCC950, on autophagy and apoptosis under hypoxia. Neonatal mice were exposed to hyperoxia for 5 days to establish oxygen-induced retinopathy (OIR) model. Intravitreal injection of MCC950 was given, and then autophagy and apoptosis markers were assessed. Retinal autophagy, apoptosis, and related pathways were evaluated by western blot, immunofluorescent labeling, transmission electron microscopy, and TUNEL assay. Autophagic activity in Müller glia after NLRP3 inflammasome inhibition, together with its influence on photoreceptor death, was studied using western blot, immunofluorescence staining, mRFP-GFP-LC3 adenovirus transfection, cell viability, proliferation, and apoptosis assays. Results showed that activation of NLRP3 inflammasome in Müller glia was detected in OIR model. MCC950 could improve impaired retinal autophagic flux and attenuate retinal apoptosis while it regulated the retinal AMPK/mTOR/ULK-1 pathway. Suppressed autophagy and depressed proliferation capacity resulting from hypoxia was promoted after MCC950 treatment in Müller glia. Inhibition of AMPK and ULK-1 pathway significantly interfered with the MCC950-induced autophagy activity, indicating MCC950 positively modulated autophagy through AMPK/mTOR/ULK-1 pathway in Müller cells. Furthermore, blockage of autophagy in Müller glia significantly induced apoptosis in the cocultured 661W photoreceptor cells, whereas MCC950 markedly preserved the density of photoreceptor cells. These findings substantiated the therapeutic potential of MCC950 against impaired autophagy and subsequent apoptosis under hypoxia. Such protective effect might involve the modulation of AMPK/mTOR/ULK-1 pathway. Targeting NLRP3 inflammasome in Müller glia could be beneficial for photoreceptor survival under hypoxic conditions.

Modified Danzhi XiaoyaoSan inhibits neuroinflammation via regulating TRIM31/NLRP3 inflammasome in the treatment of CUMS depression

The NLRP3 inflammasome is critically involved in the development of depression. The E3 ubiquitin ligase TRIM31 negatively regulates this process by promoting the degradation of NLRP3 through the ubiquitin-proteasome pathway. Modified Danzhi Xiaoyaosan (MDZXYS) has shown good therapeutic effect in both preclinical and clinical depression treatments, yet the underlying mechanisms of its antidepressant effects are not fully understood. In the present study, we aimed to explore the antidepressant mechanisms of MDZXYS, focusing on NLRP3 activation and ubiquitin-mediated degradation. We employed rats with depression induced by chronic unpredictable mild stress (CUMS) and conducted various behavioral tests, including the sucrose preference, forced swimming, and open field tests. Neuronal damage in CUMS-treated rats was assessed using Nissl staining. We measured proinflammatory cytokine levels using ELISA kits and analyzed NLRP3/TRIM31 protein expression via Western blotting and immunofluorescence staining. Our results disclosed that MDZXYS reversed CUMS-induced depression-like behaviors in rats, reduced proinflammatory cytokine levels (IL-1β), and ameliorated neuronal damage in the prefrontal cortex. Additionally, CUMS activated the NLRP3 inflammasome in the prefrontal cortex and upregulated the protein expression of TRIM31. After MDZXYS administration, the expression of NLRP3 inflammasome-associated proteins was reduced, while the expression level of TRIM31 was further increased. Through co-localized immunofluorescence staining, we observed a significant elevation in the co-localization expression of NLRP3 and TRIM31 in the prefrontal cortex of the MDZXYS group. These findings suggest that inhibiting NLRP3 inflammasome-mediated neuroinflammation by modulating the TRIM31signaling pathway may underlie the antidepressant effects of MDZXYS, and further support targeting NLRP3 as a novel approach for the prevention and treatment of depression.

Glibenclamide Prevents Inflammation by Targeting NLRP3 Inflammasome Activation in vitro

Glibenclamide Prevents Inflammation by Targeting NLRP3 Inflammasome Activation in vitro

Targeting NLRP3 Inflammasome: Structure, Function, and Inhibitors.

Inflammasomes are multimeric protein complexes that can detect various physiological stimuli and danger signals. As a result, they perform a crucial function in the innate immune response. The NLRP3 inflammasome, as a vital constituent of the inflammasome family, is significant in defending against pathogen invasion and preserving cellhomeostasis. NLRP3 inflammasome dysregulation is connected to various pathological conditions, including inflammatory diseases, cancer, and cardiovascular and neurodegenerative diseases. This profile makes NLRP3 an applicable target for treating related diseases, and therefore, there are rising NLRP3 inhibitors disclosed for therapy. Herein, we summarized the updated advances in the structure, function, and inhibitors of NLRP3 inflammasome. Moreover, we aimed to provide an overview of the existing products and future directions for drug research and development.

Targeting NLRP3 signaling reduces myocarditis-induced arrhythmogenesis and cardiac remodeling

BackgroundMyocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear.MethodsRats with myosin peptide–induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat’s RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca2+ transients, and Ca2+-modulated protein expression in individual myocytes isolated from the RVOTs.ResultsThe LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca2+ transients, lower L-type Ca2+ currents, larger late Na+ currents, larger Na+–Ca2+ exchanger currents, higher reactive oxygen species levels, and higher Ca2+/calmodulin-dependent protein kinase II levels than did those of the control and treatment groups.ConclusionMyocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling.

Dual-responsive nanocarriers for efficient cytosolic protein delivery and CRISPR-Cas9 gene therapy of inflammatory skin disorders.

Developing protein drugs that can target intracellular sites remains a challenge due to their inadequate membrane permeability. Efficient carriers for cytosolic protein delivery are required for protein-based drugs, cancer vaccines, and CRISPR-Cas9 gene therapies. Here, we report a screening process to identify highly efficient materials for cytosolic protein delivery from a library of dual-functionalized polymers bearing both boronate and lipoic acid moieties. Both ligands were found to be crucial for protein binding, endosomal escape, and intracellular protein release. Polymers with higher grafting ratios exhibit remarkable efficacies in cytosolic protein delivery including enzymes, monoclonal antibodies, and Cas9 ribonucleoprotein while preserving their activity. Optimal polymer successfully delivered Cas9 ribonucleoprotein targeting NLRP3 to disrupt NLRP3 inflammasomes in vivo and ameliorate inflammation in a mouse model of psoriasis. Our study presents a promising option for the discovery of highly efficient materials tailored for cytosolic delivery of specific proteins and complexes such as Cas9 ribonucleoprotein.

The Impact of NLRP3 Inflammasome on Osteoblasts and Osteogenic Differentiation: A Literature Review.

Osteoblasts (OBs), which are a crucial type of bone cells, derive from bone marrow mesenchymal stem cells (MSCs). Accumulating evidence suggests inflammatory cytokines can inhibit the differentiation and proliferation of OBs, as well as interfere with their ability to synthesize bone matrix, under inflammatory conditions. NLRP3 inflammasome is closely associated with cellular pyroptosis, which can lead to excessive release of pro-inflammatory cytokines, causing tissue damage and inflammatory responses, however, the comprehensive roles of NLRP3 inflammasome in OBs and their differentiation have not been fully elucidated, making targeting NLRP3 inflammasome approaches to treat diseases related to OBs uncertain. In this review, we provide a summary of NLRP3 inflammasome activation and its impact on OBs. We highlight the significant roles of NLRP3 inflammasome in regulating OBs differentiation and function. Furthermore, current available strategies to affect OBs function and osteogenic differentiation targeting NLRP3 inflammasome are listed and analyzed. Finally, through the prospective discussion, we seek to provide novel insights into the crucial role of NLRP3 inflammasome in diseases related to OBs and offer valuable information for devising treatment strategies.

Immunomodulation in allergic rhinitis: Insights from Th2 cells and NLRP3/IL-18pathway.

Allergic rhinitis (AR) is characterized by nasal symptoms such as rubbing and sneezing, often triggered by allergen exposure. The purpose of this study is to dissect the roles of NLRP3-mediated immune modulation and macrophage pyroptosis in modulating T cell differentiation within the context of ovalbumin (OVA)-induced AR in mice. OVA-induced AR was established in mice, evaluating nasal symptoms, macrophage infiltration, cytokine levels, and T cell differentiation. Manipulations using NLRP3-/-, ASC-/- mice, clodronate liposome treatment, and NLRP3 inhibitor MCC950 were performed to assess their impact on AR symptoms and immune responses. Following OVA stimulation, increased nasal symptoms were observed in the OVA group along with augmented GATA3 expression and elevated IL-4 and IL-1b levels, indicative of Th2 polarization and cellular pyroptosis involvement. NLRP3-/- and ASC-/- mice exhibited reduced CD3+ T cells post OVA induction, implicating cellular pyroptosis in AR. Macrophage depletion led to decreased IgE levels, highlighting their involvement in allergic responses. Further investigations revealed enhanced macrophage pyroptosis, influencing Th1/Th2 differentiation in AR models. IL-18 released through NLRP3-mediated pyroptosis induced Th2 differentiation, distinct from IL-1b. Additionally, MCC950 effectively mitigated AR symptoms by modulating Th2 responses and reducing macrophage infiltration. This comprehensive study unravels the pivotal role of NLRP3-mediated immune modulation and macrophage pyroptosis in Th1/Th2 balance regulation in OVA-induced AR. Targeting NLRP3 pathways with MCC950 emerged as a promising strategy to alleviate AR symptoms, providing insights for potential therapeutic interventions in AR management.