Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies

Abstract

Inflammasomes are multimeric protein complexes, sensors of intracellular danger signals, and crucial components of the innate immune system, with the NLRP3 inflammasome being the best characterized among them. The increasing scientific interest in the mechanisms interconnecting inflammation and tumorigenesis has led to the study of the NLRP3 inflammasome in the setting of various neoplasms. Despite a plethora of data regarding solid tumors, NLRP3 inflammasome's implication in the pathogenesis of hematological malignancies only recently gained attention. In this review, we investigate its role in normal lymphopoiesis and lymphomagenesis. Considering that lymphomas comprise a heterogeneous group of hematologic neoplasms, both tumor-promoting and tumor-suppressing properties were attributed to the NLRP3 inflammasome, affecting neoplastic cells and immune cells in the tumor microenvironment. NLRP3 inflammasome-related proteins were associated with disease characteristics, response to treatment, and prognosis. Few studies assess the efficacy of NLRP3 inflammasome therapeutic targeting with encouraging results, though most are still at the preclinical level. Further understanding of the mechanisms regulating NLRP3 inflammasome activation during lymphoma development and progression can contribute to the investigation of novel treatment approaches to cover unmet needs in lymphoma therapeutics.

Keywords: NLRP3; inflammasome; inflammatory signaling; lymphoma; lymphomagenesis; lymphopoiesis; pyroptosis.

Figure 1

The NLRP3 inflammasome structure. Three main components comprise the NLRP3 inflammasome: (i) NLRP3, which acts as a sensor and comprises an LRR domain, a NACHT domain, and a PYD; (ii) ASC, which acts as an adaptor and comprises a PYD and a CARD; (iii) pro-caspase-1, which comprises a CARD and caspase-1. The ASC adaptor forms a speck-like structure that binds the NLRP3 sensor to the pro-caspase-1 component through PYD-PYD and CARD-CARD interactions. Multiple ASC dimers can further polymerize, forming a supramolecular assembly, the NLRP3 inflammasome complex. ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase activation and recruitment domain; LRR, leucine-rich repeats; NACHT, NAIP (neuronal apoptosis inhibitor protein), C2TA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from Podospora anserina), TP1 (telomerase-associated protein); NLRP3, Nod-like receptor family pyrin domain containing 3; PYD, pyrin domain. Created with BioRender.com. https://app.biorender.com/ (accessed on 2 January 2024).

Figure 2

NLRP3 inflammasome complex canonical activation and downstream responses. The activation process of the NLRP3 inflammasome consists of two main signals: (i) the priming signal, which is mainly induced by PAMP or DAMP recognition by TLRs and leads to NF-κΒ-mediated transcriptional upregulation of NLRP3, pro-IL-1β and pro-IL-18; (ii) the activation signal, which is induced by various stimuli, including extracellular ATP, pore-forming toxins and extracellular agglomerates (monosodium urate crystals, cholesterol crystals, asbestos, silica), that lead to molecular or cellular events, namely K⁺ efflux, Ca²⁺ flux, ROS generation, and lysosomal damage, known to activate the NLRP3 inflammasome. Inflammasome activation leads to auto-cleavage and formation of the active caspase-1, which, in turn, proteolytically cleaves its substrates pro-IL-1β, IL-18, and GSDMD. The cleaved bioactive IL-1β and IL-18 are subsequently released extracellularly, resulting in an inflammatory response, while the cleaved GSDMD-N polymerizes to form transmembrane pores, leading to pyroptosis. ASC, apoptosis-associated speck-like protein containing a CARD (caspase activation and recruitment domain); CLIC, chloride intracellular channel; DAMPs, damage-associated molecular patterns; IL, interleukin; GSDMD, gasdermin D; GSDMD-N, gasdermin D N-terminal; NF-κΒ; nuclear factor kappa-light-chain-enhancer of activated B-cells; NLRP3, Nod-like receptor family pyrin domain containing 3; PAMPs, pathogen-associated molecular patterns; TLR, toll-like receptor; TNF, tumor necrosis factor; TNF-R, TNF receptor. Created with BioRender.com. “https://app.biorender.com/ (accessed on 2 January 2024)”.

Figure 3

Proposed mechanisms of NLRP3 inflammasome implication in the pathogenesis and progression of B-cell non-Hodgkin lymphomas. BAFF, B-cell activating factor; IFN-γ, interferon γ; JAK, Janus kinase; IL, interleukin; NLRP3, Nod-like receptor family pyrin domain containing 3; PD-1, programmed cell death protein; PD-L1, programmed death-ligand 1; R, receptor; STAT3, signal transducer and activator of transcription 3. Created with BioRender.com. “https://app.biorender.com/ (accessed on 2 January 2024)”.

Figure 4

The effects of NLRP3 inflammasome activation and its effector cytokines on lymphoma cells (A) and immune cells of the tumor microenvironment (B). (A) IL-18 and IL-1β released after NLRP3 inflammasome activation interact with their receptors on lymphoma cells, inducing signaling pathways that promote the expression of genes related to apoptosis inhibition, survival, and proliferation. (B) The pro-inflammatory cytokines secreted after NLRP3 inflammasome activation both in lymphoma cells and immune cells favor the accumulation of immunosuppressive immune cell subpopulations and promote effector T-cell exhaustion, contributing overall to immune evasion of the lymphoma cells. AP-1, activator protein 1; ATF, activating transcription factor-2; CCND1, cyclin D1; IFN, interferon; IL, interleukin; MDSC, myeloid-derived suppressor cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; PI3K, phosphoinositide 3-kinase; PD-L1, programmed death-ligand 1; PD-1, programmed cell death protein 1; STAT3, signal transducer and activator of transcription; TAM, tumor-associated macrophage; Teff, T effector; TIM-3, T-cell immunoglobulin and mucin-domain containing 3; Treg, T regulatory; TFs, transcription factors. Created with BioRender.com. “https://app.biorender.com/ (accessed on 2 January 2024)”.