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

Figure 2

Overview of inflammasome activation pathways. After recognition of PAMPs or DAMPs by the sensors, oligomerization of the complex occurs, which induces the cleavage of procaspase-1 into activated caspase-1. (a) In the canonical pathway, activation requires priming by a Toll-like receptor (TLR) ligand (e.g., LPS)—mediated by MyD88 to induce the expression of pro-IL-1b and NLRP3. Pro-IL-18 is expressed constitutively in the cell. Caspase-1 activation cleaves the pro-IL-1β inactive precursor forms, leading to the maturation and secretion to the extracellular environment. In addition, gasdermin-D cleavage also occurs, which is deposited in the cell membrane, leading to the formation of pores and causing cell death via pyroptosis. (b) In the noncanonical pathway, extracellular LPS induces the expression of pro-IL-1b and NLRP3 via the TLR4-MyD88-dependent pathway and type I interferon via the TLR4-TRIF-dependent pathway. Type I interferon provides a feedback loop and activates IFNAR to induce caspase-11 expression. Cytosolic Gram-negative bacteria deliver LPS into the cytosol when they escape the vacuole. Caspase-11 is activated following its binding to cytosolic LPS, then drives pyroptosis and activation of the noncanonical NLRP3 inflammasome Abbreviations: DAMPs, damage-associated molecular patterns; GSDMD, gasdermin-D; LPS, lipopolysaccharide; N-GSDMD, amino-terminal cell death domain; PAMPs, pathogen-associated molecular pattern molecules; TLR, Toll-like receptor; MyD88, myeloid differentiation primary response 88; IFNAR, type I interferon receptor.