Does elevated Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) reflect an activated NLRP3 (Nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3) inflammasome?

From the Guidelines

Elevated Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) are indicative of an activated NLRP3 inflammasome.

Key Points

• The activation of the NLRP3 inflammasome leads to the cleavage of pro-IL-1β and pro-IL-18 by caspase-1, resulting in the release of mature IL-1β and IL-18 1.
• Elevated levels of IL-1β and IL-18 have been observed in various conditions, including ischemic stroke, where the NLRP3 inflammasome is activated 1.
• The NLRP3 inflammasome can be activated by various stimuli, including mitochondrial dysfunction, oxidative stress, and the release of mitochondrial DNA (mtDNA) into the cytosol 1.
• The activation of the NLRP3 inflammasome and the subsequent release of IL-1β and IL-18 play a crucial role in the inflammatory response and can contribute to tissue damage and disease progression 1.

Evidence

• A study published in Redox Biology in 2018 found that the NLRP3 inflammasome is activated in response to mitochondrial dysfunction and oxidative stress, leading to the release of IL-1β and IL-18 1.
• Another study published in Cell Death and Differentiation in 2012 defined pyroptosis as a caspase-1-dependent cell death subroutine that is associated with the activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 1.
• A study published in Annals of the Rheumatic Diseases in 2024 found that elevated levels of IL-18 are associated with macrophage activation syndrome (MAS) and can be used as a diagnostic biomarker 1.
• A study published in Redox Biology in 2018 found that the NLRP3 inflammasome is activated in response to mitochondrial dysfunction and oxidative stress, leading to the release of IL-1β and IL-18, and that intravenous immunoglobulin (IVIg) treatment can reduce the protein levels of NLRP3 and inhibit the downstream inflammatory response 1.

From the Research

Elevated Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) Reflection of Activated NLRP3 Inflammasome

• Elevated levels of IL-1β and IL-18 are associated with the activation of the NLRP3 inflammasome, as shown in studies 2, 3, 4.
• The NLRP3 inflammasome is a multiprotein complex that activates caspase-1, leading to the maturation of IL-1β and IL-18, and the induction of pyroptosis, a form of cell death 3.
• The activation of the NLRP3 inflammasome can be triggered by diverse stimuli, including ATP, chitosan, and silica oxide (SiO2) 2.
• The ratio of IL-1β to IL-18 production can vary depending on the stimulus used to activate the NLRP3 inflammasome, suggesting that the NLRP3 inflammasome response is a dynamic process 2.

Role of IL-1β and IL-18 in Inflammasome Activation

• IL-1β is an important mediator of the acute phase response to infections and tissue damage, while IL-18 plays a role in the activation and tailoring of the adaptive immune response 2.
• The production of IL-1β and IL-18 is regulated by the NLRP3 inflammasome, and their levels are increased in response to NLRP3 inflammasome activation 4, 5.
• The levels of IL-1β and IL-18 have been shown to be correlated with the progression of diabetic nephropathy in patients with type 2 diabetes, suggesting a role for the NLRP3 inflammasome in the pathogenesis of this disease 6.

Regulation of NLRP3 Inflammasome Activation

• The regulation of NLRP3 inflammasome activation is complex and involves multiple pathways, including the regulation of caspase-1 activity and pyroptosis 3, 4.
• Type I interferons have been shown to regulate the production of IL-1β and IL-18 in response to NLRP3 inflammasome activation, suggesting a role for these cytokines in the regulation of the inflammasome response 5.