Abstract
Cellular lipids determine membrane integrity and fluidity and are being increasingly recognized to influence immune responses. Cellular cholesterol requirements are fulfilled through biosynthesis and uptake programs. In an intricate pathway involving the lysosomal cholesterol transporter NPC1, the sterol gets unequally distributed across intracellular compartments. By using pharmacological and genetic approaches targeting NPC1, we reveal that blockade of cholesterol trafficking through the late endosome-lysosome pathway blunts NLRP3 inflammasome activation. Altered cholesterol localization at the plasma membrane (PM) in Npc1-/- cells abrogated AKT-mTOR signaling by TLR4. However, the inability to activate the NLRP3 inflammasome was traced to perturbed cholesterol trafficking to the ER but not the PM. Accordingly, acute cholesterol depletion in the ER membranes by statins abrogated casp-1 activation and IL-1β secretion and ablated NLRP3 inflammasome assembly. By contrast, assembly and activation of the AIM2 inflammasome progressed unrestricted. Together, this study reveals ER sterol levels as a metabolic rheostat for the activation of the NLRP3 inflammasome.
Highlights
The inflammasome is a multiprotein complex that plays critical roles in infectious, inflammatory, and autoimmune diseases
By using pharmacological and genetic tools, we demonstrate that selective perturbation of the cellular cholesterol trafficking in macrophages ablates inflammasome activation
Lysosomal sterol accumulation dampens inflammasome activation Homeostatic cholesterol trafficking is important as its distribution among subcellular organelles upholds vital housekeeping functions, and is critically dependent on lysosomal cholesterol transporter Niemann-Pick C1 (NPC1)
Summary
The inflammasome is a multiprotein complex that plays critical roles in infectious, inflammatory, and autoimmune diseases. The NLRP3 inflammasome is the most characterized inflammasome in terms of the diverse stimuli that are known to activate it. Activation of the NLRP3 inflammasome requires assembly of NLRP3 and caspase-1 (casp-1) bridged together through the adaptor protein ASC, wherein casp-1 undergoes autoproteolytic processing. Active casp-1 cleaves precursor forms of cytokines interleukin (IL)–1β and IL-18, which can be secreted (Man and Kanneganti, 2015; Hamilton et al, 2017). Casp-1 cleaves gasdermin D (GSDMD), making its N-terminal pore-forming domain active, leading to cell rupture (Kayagaki et al, 2015; Shi et al, 2015). Endogenous, and environmental stimuli are known to activate the NLRP3 inflammasome, implying that these stimuli do not bind NLRP3 directly but likely converge on shared upstream pathways.
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