The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation

Abstract

The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1 −/− macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and “dicarboxypropylated” C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.

Ketamine and Propofol Protect Neuron Cells from Oxygen-Glucose Deprivation-Induced Injury through SAPK/JNK Signalling Pathway

“…Previously reported results showed that ketamine and propofol can suppress LPS-induced upregulation of IL-1beta and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in glia cells and brains [ 15 , 16 ]. IL-1beta is a proinflammatory cytokine and critically participates in cell activation and death of macrophage pyroptosis [ 17 , 18 ]. TNF-alpha, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and IFN-gamma are a potent inducer of neuron, microglia, and astroglia apoptosis after hypoxia-ischemia and inflammation [ 1 , 19 ].…”

Downstream of gasdermin D cleavage, a Ragulator-Rag-mTORC1 pathway promotes pore formation and pyroptosis

“…A link between metabolism and cell death phenotypes has been investigated in many prior studies, including recent work demonstrating that the inflammasome components NLRP3 and GSDMD can be post-translationally modified by TCA cycle intermediates (Hooftman et al, 2020; Humphries et al, 2020). Moreover, metabolic dysfunction and mitochondrial damage have been considered to initiate death pathway signaling events upstream of apoptosome and inflammasome activities (Andersen and Kornbluth, 2013; Prochnicki and Latz, 2017).…”

Electrophile Modulation of Inflammation: A Two-Hit Approach

“…2The matrix pH changes during cellular respiration, yielding more reactive thiol groups Interestingly, itaconate-dependent activation of NRF2 was sufficient to inhibit IL-1β transcription in the context of LPS-activated macrophages. Hooftman et al expanded upon this important body of work by characterizing the effect that this immunomodulatory metabolite has on inflammasome-dependent IL-1β production and maturation [112]. More specifically, itaconate was found to alkylate Cys 548 on NLRP3, thereby inhibiting the interaction between this protein and NEK7, a partner required for inflammasome activation.…”

“…More specifically, itaconate was found to alkylate Cys 548 on NLRP3, thereby inhibiting the interaction between this protein and NEK7, a partner required for inflammasome activation. Additional research will be needed to evaluate if itaconate can be used as a therapeutic to treat NLRP3-driven inflammatory pathologies [111,112].…”