The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia

Urwanisch, Laura; Luciano, Michela; Horejs‐Hoeck, Jutta

doi:10.3390/ijms22031271

Cited by 20 publications

(12 citation statements)

References 140 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Current reports of the aberrant expression of NLRP3 inflammasome in the marrow cells have shown NOCs to be a catalyst for the pathogenicity of leukemia 9,52 . In resemblance with the reports on the status of NLRP3 in leukemia, we observed an over expression of NLRP3 inflammasome in the BM cells of ENU‐induced leukemic mice 7,53,54 . Even though, WDL has been delineated to inhibit NLRP3 inflammasome expression in other disease models, the elaborated mechanism of WDL or the crude extract of EP has never been explored in case of leukemia 25,26,34 .…”

Section: Discussionsupporting

confidence: 64%

Environmental pollutant N‐N′ethylnitrosourea‐induced leukemic NLRP3 inflammasome activation and its amelioration by Eclipta prostrata and its active compound wedelolactone

Bhattacharyya¹,

Law²

2021

Environmental Toxicology

View full text Add to dashboard Cite

Environmental exposure of N‐nitroso compounds (NOCs) from various sources like tobacco smoke, pesticides, smoked meat, and rubber manufacturing industries has been an alarming cause of carcinogenesis. Neonatal exposure to the carcinogenic N‐N′ethylnitrosourea (ENU), a NOC has been established to cause leukemogenesis. Our world is constantly battling against cancer with consistent investigations of new anti‐cancer therapeutics. Plant derived compounds have grasped worldwide attention of researchers for their promising anti‐cancer potentials. Eclipta prostrata is one such ayurvedic herb, renowned for its anti‐inflammatory properties. Currently, it has been explored in various cancer cell lines to establish its anti‐cancer effect, but rarely in in‐vivo cancer models. Wedelolactone (WDL), the major coumestan of E. prostrata is recognized as an inhibitor of IKK, a master regulator of the NF‐kB inflammatory pathway. As persistent inflammation and activated inflammasome contribute to leukemogenesis, we tried to observe anti‐leukemogenic efficacy of E. prostrata and its active compound WDL on the marrow cells of ENU induced experimental leukemic mice. Treatment groups were administered an oral gavage at a dose of 1200 mg/kg and 50 mg/kg b.w of crude extract and WDL respectively for 4 weeks. Various parameters like hemogram, survivability, cytological and histological investigations, migration assay, cell culture, flowcytometry and confocal microscopy were taken into consideration pre‐ and post‐treatment. Interestingly, the plant concoction portrayed maximum effects in comparison to WDL alone. The study suggests E. prostrata and WDL as vital complementary adjuncts for anti‐inflammasome mechanism in ENU‐induced leukemia.

show abstract

Section: Discussionsupporting

confidence: 64%

Environmental pollutant N‐N′ethylnitrosourea‐induced leukemic NLRP3 inflammasome activation and its amelioration by Eclipta prostrata and its active compound wedelolactone

Bhattacharyya¹,

Law²

2021

Environmental Toxicology

View full text Add to dashboard Cite

show abstract

“…Inflammasome is an important part of the central immune system, which has three components: pattern recognition receptor (PRR), apoptosis-associated speck-like protein (ASC), and caspase-1 ( Shuo et al, 2018 ). NLRP3 is an inflammatory complex, which exists in microglia, and its over-activation may lead to many diseases ( Urwanisch et al, 2021 ). In the presence of stimuli, sustained activation of microglia will lead to the production of IL-1β and IL-18 mediated by NLRP3, both are powerful pro-inflammatory factors ( Ramesh et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Edaravone Plays Protective Effects on LPS-Induced Microglia by Switching M1/M2 Phenotypes and Regulating NLRP3 Inflammasome Activation

Dai

Zhou

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Parkinson’s disease is a neurodegenerative disorder in which activated microglia may appear prior to motor symptoms, but the specific therapeutic mechanisms remain unclear. This study investigated the potential effects of Edaravone (EDA) on M1/M2 polarization of microglia in rats with dopaminergic neurons damage induced by lipopolysaccharide (LPS) and its mechanism. Rats were randomly grouped as the following (n = 10): Control, EDA alone (10 mg/kg), LPS-model (LPS 5 μg), LPS + EDA (5 mg/kg) and LPS + EDA (10 mg/kg). After intragastric administration of EDA once a day for seven consecutive days, LPS was injected into SN pars unilaterally. Rotarod test, pole test, and traction test were used to analyze the intervention effect of EDA on neurobehavioral function in rats. Protein expression levels of TH, TNF-α, Arg-1, Iba-1, NLRP3 and caspase-1 were measured by immunofluorescence staining and western blot. In vitro, BV-2 cells were treated with LPS (100 ng/ml) before adding different doses of EDA. Levels of inflammatory cytokines in culture medium were detected by ELISA. Western blot and immunofluorescence were used to evaluate microglial activation and polarization. First, rotarod test, pole test, and traction test all showed that EDA mitigated motor dysfunction of PD rats. Second, pathological analysis suggested that EDA inhibited LPS-induced microglial activation and remitted declines of dopaminergic neurons. In addition, EDA shifted M1 pro-inflammatory phenotype of microglia to M2 anti-inflammatory state, while decreased expression of M1 markers (TNF-α and IL-1β) and facilitated expression of M2 markers (Arg-1 and IL-10). EDA suppressed inflammatory responses through inhibiting the expression of pro-inflammatory factors (IL-1β, IL-18 and NO), but the neuroprotective effects were invalid while siRNA NLRP3 existed. In conclusion, these results indicated that EDA could improve neurobehavioral functions and play anti-neuroinflammatory roles in PD rats, possibly by inhibiting NLPR3 inflammasome activation and regulating microglia M1/M2 polarization.

show abstract

“…While unbalanced release of pro-inflammatory cytokines such as IL-1, IL-6, TNF-α and GM-CSF has been frequently reported in AML, 34 a leukemogenic role for the NLRP3 inflammasome — the central hub of innate immunity mediating the release of pro-inflammatory factors — has only recently been suggested. 8,35,36…”

Section: Discussionmentioning

confidence: 99%

The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia

Luciano

Blöchl

Vetter

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1β; and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2α; phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2α; phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2α; phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.

show abstract

The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia

Cited by 20 publications

References 140 publications

Environmental pollutant N‐N′ethylnitrosourea‐induced leukemic NLRP3 inflammasome activation and its amelioration by Eclipta prostrata and its active compound wedelolactone

Environmental pollutant N‐N′ethylnitrosourea‐induced leukemic NLRP3 inflammasome activation and its amelioration by Eclipta prostrata and its active compound wedelolactone

Edaravone Plays Protective Effects on LPS-Induced Microglia by Switching M1/M2 Phenotypes and Regulating NLRP3 Inflammasome Activation

The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia

Contact Info

Product

Resources

About