Inflammasome Priming in Sterile Inflammatory Disease

NLRP3 inflammasome priming requires transcriptional upregulation of NLRP3 and pro-IL-1β expression, together with post-translational modification of NLRP3 itself. Obesity and other chronic inflammatory states prime the NLRP3 inflammasome, and these constitute serious predisposing factors for inflammasome activation in sterile inflammatory disease. Microbial priming of the inflammasome could potentially drive crosstalk between the environment and the development of autoinflammatory disease. Inflammasome priming is not limited to immune cells, and can contribute significantly to overall pathology during chronic, low-grade inflammation. The inflammasome is a cytoplasmic protein complex that processes interleukins (IL)-1β and IL-18, and drives a form of cell death known as pyroptosis. Oligomerization of this complex is actually the second step of activation, and a priming step must occur first. This involves transcriptional upregulation of pro-IL-1β, inflammasome sensor NLRP3, or the non-canonical inflammasome sensor caspase-11. An additional aspect of priming is the post-translational modification of particular inflammasome constituents. Priming is typically accomplished in vitro using a microbial Toll-like receptor (TLR) ligand. However, it is now clear that inflammasomes are activated during the progression of sterile inflammatory diseases such as atherosclerosis, metabolic disease, and neuroinflammatory disorders. Therefore, it is time to consider the endogenous factors and mechanisms that may prime the inflammasome in these conditions. The inflammasome is a cytoplasmic protein complex that processes interleukins (IL)-1β and IL-18, and drives a form of cell death known as pyroptosis. Oligomerization of this complex is actually the second step of activation, and a priming step must occur first. This involves transcriptional upregulation of pro-IL-1β, inflammasome sensor NLRP3, or the non-canonical inflammasome sensor caspase-11. An additional aspect of priming is the post-translational modification of particular inflammasome constituents. Priming is typically accomplished in vitro using a microbial Toll-like receptor (TLR) ligand. However, it is now clear that inflammasomes are activated during the progression of sterile inflammatory diseases such as atherosclerosis, metabolic disease, and neuroinflammatory disorders. Therefore, it is time to consider the endogenous factors and mechanisms that may prime the inflammasome in these conditions. Mice with a genetic deficiency for ApoE that is required for normal catabolism of triglyceride-rich lipoproteins. an adaptor protein used by many cytoplasmic PRRs to engage with caspase-1 in an inflammasome complex. the formation of abnormal lipid masses in the arterial wall that are associated with immune cell infiltration. a cell-intrinsic mechanism to catabolize the endogenous components of a components. direct ligands for PRRs that are generated by dead or dying cells. decreased oxygen availability. increasing NLRP3 and pro-IL-1β expression to a level that is sufficient for oligomerization and activation to proceed if triggered. a metabolite with antibacterial effects; produced in macrophages. one of a family of cell-surface receptors triggered by ATP. pigment granule composed of lipids that accumulate in lysosomes. an ‘inflammatory’ macrophage subtype; it can be generated by stimulation with LPS and IFN-γ. an ‘anti-inflammatory’ macrophage subtype (or ‘activated’); can be generated by stimulation with IL-4. direct ligands for PRRs that are of microbial origin, otherwise known as MAMPs. receptors for ligands or signals that activate immune pathways. an inherited condition associated with inflammatory manifestations that can be periodic in nature. programmed cell death mediated by mixed-lineage kinase domain-like (MLKL; necroptosis) or caspase substrate gasdermin D (GSDMD; pyroptosis). the executioner caspase of the non-canonical inflammasome is caspase-11 (mouse) or caspase-4/5 (human) rather than the canonical inflammasome (caspase-1). cell-surface import receptor for ligands such as low-density lipoprotein (LDL). inflammatory conditions that are not associated with a pathogenic infection transcription factors that bind to DNA motifs commonly associated with enzymes regulating sterol biosynthesis. a protein found as insoluble deposits in the brains of individuals with Parkinson’s disease. inflammatory T helper cell defined by the production of IL-17.