Insights Regarding the Role of Inflammasomes in Leukemia: What Do We Know?

Figure 3

Inflammasome effects on tumor progression and inhibition in leukemias. Antitumorigenic: (1) the deletion of NLRP3 in leukemic cells can decrease the proliferation of blasts through the neutralization of the cytokine IL-1β; (2) the RIPK3 protein suppresses the proliferation of leukemic cells through the activation of NLRP3 and induces apoptosis via TNFR; (3) NLRP3 activation in BMDMs via IL-1β secretion promotes the proliferation of IFN-γ-producing Th1 cells with anti-leukemic effects; (4) NLRP3 overexpression induced by ATRA treatment cause pyroptosis of leukemic cells; moreover, DPP9 inhibition enhances CARD8 activation also culminating in this cell death; and (5) NLRP3 overexpression negatively regulates the P2X7R receptor, inhibiting the proliferation of leukemic cells and inducing apoptosis. Protumorigenic: (1) IRE1α protein increases NLRP1 expression in leukemic cells and contributes to proliferation and survival; (2) the PKC-CREB pathway regulates NLRP1 expression in leukemic cells and possibly contributes to proliferation; (3) the IL-1β cytokine stimulates an increase in cell proliferation; and (4) prevents the differentiation of umbilical cord blood (UCB)-CD34⁺ into NK cells. In addition, it also (5) stimulates the expression of adhesion molecules to promote the recruitment of leukemic cells by epithelial cells; (6) DCs activated by the cytokine IL-18 promotes the differentiation of TCD4+ lymphocytes into Tregs; (7) NLRP3 collaborates with AHR for imbalance in Th1 profile response; (8) increased transcription of CASP1 and NLRP3 results in cleavage of glucocorticoid receptors. Abbreviations: ⊥ = inhibition; ↓ = activation; AHR, aryl hydrocarbon receptor; ASC, apoptosis-associated speck-like protein; ATRA, all-trans-retinoic acid; BMDMs, bone-marrow-derived macrophage; cAMP, cyclic adenosine monophosphate; CREB, cAMP-response element-binding protein; DC, dendritic cell; DPP9, dipeptidyl peptidase 9; GR, glucocorticoid receptor; GSDMD, gasdermin-D; GSDMD-N, GSDMD amino-terminal cell death domain; IFN-γ, gamma interferon; IL-18, interleukin-18; IL-1β, interleukin-1β; IREIα, endoplasmic reticulum stress sensor; LT, lymphocyte; NK, natural killer cell; NLRP1, NOD-like receptor protein 1; NLRP3, NOD-like receptor protein 3; P, phosphorylation P2X7R, purinergic P2X7 receptor; PKC, protein kinase C ROS, reactive oxygen species; tBID, proapoptotic protein; Th1, type 1 T helper (Th1); Th22, type 22 T helper (Th22); TNFR, tumor necrosis factor receptor; Tregs, regulatory T cells; ?, Influence on the known.