Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies
Abstract
:1. Introduction
2. The NLRP3 Inflammasome: Structure, Activation, and Downstream Effects
2.1. Structure
2.2. Priming and Activation
2.3. Downstream Response
3. The NLRP3 Inflammasome in Lymphocyte Development
3.1. Normal Lymphopoiesis Overview
3.2. The NLRP3 Inflammasome in B-Cell Lymphopoiesis
3.3. The NLRP3 Inflammasome in T-Cell Lymphopoiesis
4. The NLRP3 Inflammasome in Lymphomagenesis
4.1. B-Cell NHLs
4.1.1. NLRP3 Inflammasome Activation Contributes to B-Cell NHL Development via Its Effector Cytokines
4.1.2. The Effect of NLRP3 Inflammasome Activation in the B-Cell NHL Microenvironment
4.1.3. Deciphering the Drivers of NLRP3 Inflammasome Activation in B-Cell NHL
4.2. T and NK-Cell Lymphomas
5. Exploring the Crosstalk of Tripartite Motif (TRIM) Family Proteins and NLRP3 Inflammasome Activation in Lymphoma
6. Molecular Pathways by Which NLRP3 Inflammasome Affects Lymphoma Cells and the Immune TME
6.1. Effects on Lymphoma Cells
6.2. Effects on the Immune TME
7. NLRP3 Inflammasome Signaling in Lymphoid Premalignant Conditions
8. Therapeutic Targeting of NLRP3 in Lymphoma
9. Discussion
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Lymphoma Subtype | Type of Sample Studied | Effect of NLRP3 Inflammasome or Related Molecules | Studied NLRP3 Inflammasome Components or Related Molecules | Proposed Mechanism | Findings | Possible Clinical Relevance | Ref. |
---|---|---|---|---|---|---|---|
DLBCL | Pfeiffer cell line | Tumor-promoting | IL-18 | NLRP3 inflammasome activation induces:
| NLRP3 inflammasome activation inhibited dexamethasone-induced apoptosis via shifting the balance of BCL-2/BAX expression | Resistance to dexamethasone | [83] |
DLBCL | 73 patients: serum samples | Tumor-promoting | IL-18 | IL-18-mediated pro-tumorigenic effect | Higher mean IL-18 levels correlated with lower CR (p = 0.465) and 3-year DFS rates (p = 0.127) after R-CHOP Lower mean IL-18 levels correlated with more favorable OS rates (p = 0.008) | Prognostic value for survival and treatment response | [85] |
DLBCL | 35 patients and 35 healthy controls: lymphoid tissue samples | Tumor-promoting | IL-18, PD-L1 | IL-18-mediated pro-tumorigenic effect IL-18-mediated immune exhaustion | Higher IL-18 expression in DLBCL tissues compared to normal lymphoid tissues Higher IL-18 expression in DLBCLs with non-GCB phenotype compared to those with GCB phenotype Higher PD-L1 expression in DLBCL tissues compared to normal lymphoid tissues | Association with more aggressive disease Association with immune exhaustion—possible application for ICB therapy | [86] |
DLBCL | Cell lines, murine model | Tumor-promoting | NLRP3, PD-L1, pSTAT3 | NLRP3 induced IL-18 secretion drives PD-L1 upregulation via pSTAT3 | NLRP3 inflammasome activation led to PD-L1 upregulation and T-cell decrease NLRP3 inflammasome blockade suppressed lymphoma growth and ameliorated antitumor immunity by downregulating PD-L1 in the TME and decreasing the proportion of immunosuppressive immune cells pSTAT3 protein levels decreased after IL-18 and NLPR3 inflammasome inhibition | Association with immune exhaustion—possible application for ICB therapy | [86] |
DLBCL | GEO and TCGA gene expression datasets for DLBCL and normal B cells | Tumor-promoting | PRGs | Upregulated: PYCARD, IRF1, GZMA, GSDMD, GSDMC, GPX4, CHMP2A, CASP5, CASP1, IL-18 Amplified CNV status: BAK1 Three distinct clusters identified and associated with prognosis | Risk stratification | [102] | |
DLBCL | TCGA dataset: dataset including 48 tissue samples of DLBCL patient | Tumor-promoting | Multiple inflammasome components | NLRP3 inflammasome upregulation in macrophages drives a proinflammatory TME that favors lymphomagenesis | Significant upregulation in AIM2, ALK, IRF3, 4 and 8, NFKB1 and 2, NOD2, NLRP1 and 3, CASP1 and 5, CARD8 and 9 in M0 and M1 macrophages | [100] | |
Aggressive B-cell NHL | 46 patients and 20 healthy controls: serum samples | Inconclusive | IL-18 | No significant difference in IL-18 serum levels between patients and controls (p = 0.261) Νο difference in IL-18 serum levels before and after chemotherapy Higher IL-18 serum levels were higher in patients with higher LDH compared to those with normal LDH (p = 0.045) | Possible association with high-risk lymphoma features | [88] | |
B-cell NHL | 281 patients with B-cell NHL (BM samples) and 385 healthy controls (PB samples) | Tumor-promoting | IL-1β, IL-18, NF-κΒ, CARD8 | NF-κΒ mediated NLRP3 inflammasome activation IL-18-mediated pro-tumorigenic effect | IL-18 (rs1946518) and NF-κB-94 ins/del (rs28362491) gene polymorphisms contributed to increased risk for B-cell NHL (p < 0.0001 and p = 0.0029, respectively) The AA genotype of the CARD8 rs2043211 polymorphism correlated with poorer survival (p = 0.0381) Τhe TT genotype of CARD8 (rs2043211) was observed in patients with higher LDH levels, clinical stages III-IV, and IPI scores 3–5 | Biomarkers for lymphoma susceptibility Possible association with high-risk lymphoma features | [101] |
B-cell NHL | Primary B cells and lymphoma cell lines | Not investigated Possibly tumor-promoting | NLRP3, caspase-1, IL-1β, cIAP1-TRAF2, Src | BAFF/BAFF-R axis induces cIAP1-TRAF2-mediated NLRP3 priming signals and Src activity-dependent ROS mediated NLRP3 inflammasome activation signals | Treatment with BAFF led to an increase in NLRP3 mRNA expression but also in increased NLRP3 inflammasome activation (as proven by the increase in active caspase-1 and IL-1β levels) | [113] | |
NHL | 27 patients: serum samples | Tumor-promoting | IL-18 | IL-18-mediated pro-tumorigenic effect | Patients with IL-18 serum levels >2000 pg/mL compared to those with IL-18 serum levels <1000 pg/mL showed lower CR rates (33.3% versus 85.7%) and lower median OS (3.5 months versus 45.5 months) after CHOP chemotherapy | Prognostic value for survival and treatment response | [84] |
MALT lymphoma | 45 SS patients and 25 sicca controls: salivary gland tissue specimens | Tumor-promoting | P2X7R, NLRP3, caspase-1, IL-18, IL-1β | P2X7R-mediated NLRP3 inflammasome activation IL-18-mediated pro-tumorigenic effect | Higher mRNA expression for P2X7R, NLRP3, caspase-1, IL-18, and IL-1β in patients with SS who developed MALT-NHL over the follow-up More pronounced P2X7R protein expression in SS patients developing MALT-NHL Three-fold higher glandular expression of IL-18 in MALT-NHL than in controls or the other patients with SS. | Biomarker for lymphoma development in SS | [89] |
MALT lymphoma | 76 SS patients, 11 non-SS disease controls, and 30 healthy controls: salivary gland tissue specimens and serum samples | Tumor-promoting | NLRP3, caspase-1, IL-18, IL-1β, ASC | Cell-free and extranuclear DNA-mediated NLRP3 inflammasome activation IL-18-mediated pro-tumorigenic effect | Systemic activation of the NLRP3 inflammasome and significantly increased serum IL-18 and ASC levels in SS patients at high risk for lymphoma development and those with established lymphoma | Biomarker for lymphoma development in SS | [118] |
MCL | 7 lymphoid tissue samples from patients | Tumor-promoting | IL-18 | IL-18-mediated pro-tumorigenic effect | IL-18 gene upregulation | Further MCL subtyping | [90] |
PEL | BJAB cells, BCBL-1 PEL cells | Not investigated Possibly tumor-promoting | Caspase-1, IL-1β, IL-18 | Activation of caspase-1 and cleavage of pro-IL-1β and pro-IL-18 detected in lymphoma cells induced by KSHV | [91] | ||
CLL/SLL | 23 patients: B cells from PB samples | Tumor-suppressive | P2X7R, ASC, NLRP3 | P2X7R-mediated NLRP3 inflammasome activation | NLRP3 overexpression correlated with inhibition of cell proliferation and induction of apoptosis NLRP3 downregulation contributed to lymphomagenesis | Biomarker for disease aggressiveness or progression | [92] |
Burkitt lymphoma | HH514-16 and CLIX-FZ cell lines | Tumor-suppressive | NLRP3, HMGB1 | HMGB1 protein sustains ZEBRA expression via the NLRP3 inflammasome | EBV lytic phase Burkitt lymphoma cells express high levels of HMGB1 HMGB1 regulates NLRP3 inflammasome-mediated ZEBRA expression | [93] | |
CTCL | 95 patients: plasma samples 20 patients: skin tissues | Tumor-promoting | IL-18, caspase-1 | Increased IL-18 level can favor skewing of CD4+ T cells to the characteristic Th2 phenotype | Increased IL-18 and caspase-1 plasma levels in patients compared to healthy controls Increased IL-18 and caspase-1 mRNA levels in skin lesions from patients compared to healthy skin | Biomarker | [120] |
CTCL | 53 patients, 12 healthy controls, 10 patients with psoriasis, 12 patients with atopic dermatitis: skin tissues | Tumor-promoting | NLRP3, IL-4 | NLRP3 translocation to the nucleus of the malignant CD4+ T cells, where it binds to the human IL-4 promoter in duces IL-4 production, which promotes the characteristic Th2 phenotype | IL-4 production mediated by NLRP3 increased with lesion severity and associated with disease progression | Association with disease severity and progression | [124] |
Sézary syndrome | 28 patients, 19 erythroderma patients, and 40 healthy donors: skin tissues, PB samples, serum samples, lymphoid tissue samples | Tumor-promoting (dependent on the affected tissue) | NLRP3, IL-1β, IL-18, AIM2, NLRP1 | IL-18-mediated pro-tumorigenic effect—though its production might not be exclusively mediated by NLRP3 inflammasome | Increased IL-1β and low IL-18 levels in the epidermal skin layer of patients Increased IL-18 expression and no difference in IL-1β in the dermal skin layers of patients compared to controls Equal NLRP3 and AIM2 expression in the skin among the different groups Increased NLRP1 expression in the skin of patients Increased IL-18 serum levels in patients Upregulation in IL-18 and downregulation in IL-1β in the LNs of patients with advanced-stage disease | Diagnostic biomarker Association with disease severity | [127] |
NK/T-cell lymphoma | 114 patients: serum samples | Tumor-promoting | IL-18 | IL-18-mediated pro-tumorigenic effect | High IL-18 serum levels associated with stage III/IV disease, presence of hemophagocytosis, and poor treatment outcomes. OS and PFS were significantly lower for the high IL-18 group compared to the low IL-18 groups (p < 0.001) High IL-18 serum levels were independently prognostic for survival in multivariate analysis | Biomarker of hemophagocytosis Prognostic biomarker | [128] |
NK/T-cell lymphoma | 3 NK/T-cell lymphomas, 7 infectious mononucleosis cases, 6 chronic active EBV infection cases: lymphoid tissue miRNA expression datasets | Not investigated | hsa-miR-372-5p | Hsa-miR-372-5p may target NIMA-related kinase 7 to regulate NLRP3 inflammasome activation | Hsa-miR-372-5p regulates the NIMA-related kinase 7 and IL-1β release | Biomarker for EBV-associated disease | [129] |
Various lymphoma subtypes (B-cell NHL, T-cell lymphoma, HL) | Lymphoma tissues: 68 patients (46 newly diagnosed, 22 treated) and 40 controls Plasma samples: 35 lymphoma patients and 15 controls | Tumor-promoting | IL-18 | IL-18-mediated pro-tumorigenic effect | Higher IL-18 mRNA (p = 0.0288) and protein levels (p < 0.0001) in tissues of newly diagnosed lymphoma patients compared to controls Decrease in IL-18 mRNA (p = 0.0366) and protein levels (p = 0.0098) in tissues of patients with remission after chemotherapy Elevated plasma IL-18 protein levels in newly diagnosed lymphoma patients compared to controls Decreased plasma IL-18 protein levels after chemotherapy remission (p = 0.0098) | Diagnostic and prognostic biomarker | [83] |
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Stergiou, I.E.; Tsironis, C.; Papadakos, S.P.; Tsitsilonis, O.E.; Dimopoulos, M.A.; Theocharis, S. Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies. Int. J. Mol. Sci. 2024, 25, 2369. https://doi.org/10.3390/ijms25042369
Stergiou IE, Tsironis C, Papadakos SP, Tsitsilonis OE, Dimopoulos MA, Theocharis S. Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies. International Journal of Molecular Sciences. 2024; 25(4):2369. https://doi.org/10.3390/ijms25042369
Chicago/Turabian StyleStergiou, Ioanna E., Christos Tsironis, Stavros P. Papadakos, Ourania E. Tsitsilonis, Meletios Athanasios Dimopoulos, and Stamatios Theocharis. 2024. "Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies" International Journal of Molecular Sciences 25, no. 4: 2369. https://doi.org/10.3390/ijms25042369
APA StyleStergiou, I. E., Tsironis, C., Papadakos, S. P., Tsitsilonis, O. E., Dimopoulos, M. A., & Theocharis, S. (2024). Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies. International Journal of Molecular Sciences, 25(4), 2369. https://doi.org/10.3390/ijms25042369