Do elevated Interleukin-1 beta (IL-1β) and very high Interleukin-18 (IL-18) levels imply activation of the NLRP3 (Nucleotide-binding domain, Leucine-rich repeat-containing family, Pyrin domain-containing 3) inflammasome?

From the Guidelines

Elevated levels of IL-1β and very high IL-18 strongly suggest NLRP3 inflammasome activation, as these cytokines are key products of the NLRP3 inflammasome pathway 1. The NLRP3 inflammasome is a protein complex that, when activated, processes pro-IL-1β and pro-IL-18 into their active forms, leading to their increased secretion. This molecular pathway is a key component of the innate immune response. NLRP3 activation occurs in response to various danger signals including pathogens, cellular stress, or sterile inflammatory triggers. Some key points to consider include:

• The recent study by 1 provides evidence that IL-18 is a sensitive and specific biomarker for adult-onset Still's disease, which is characterized by elevated IL-18 levels.
• The study found that IL-18 levels were significantly higher in patients with adult-onset Still's disease compared to healthy controls and patients with other rheumatic diseases.
• The NLRP3 inflammasome is thought to play a key role in the pathogenesis of adult-onset Still's disease, and elevated IL-18 levels are a hallmark of this condition. While these elevated cytokines provide compelling evidence of NLRP3 activation, it's essential to note that other inflammasomes (like NLRC4 or AIM2) can also contribute to IL-1β and IL-18 production, though NLRP3 is the predominant source. Confirmation of NLRP3 activation might require additional testing such as measuring ASC speck formation, caspase-1 activation, or direct assessment of NLRP3 oligomerization. Clinical context is also crucial, as NLRP3 hyperactivation is associated with autoinflammatory conditions like cryopyrin-associated periodic syndromes (CAPS), while more moderate activation occurs during normal immune responses to infection. In the context of elevated IL-1β and very high IL-18 levels, it is reasonable to suspect NLRP3 inflammasome activation, and further evaluation and management should be guided by this possibility 1.

From the FDA Drug Label

The NLRP3 protein is an important component of the inflammasome and regulates the protease caspase-1 and controls the activation of IL-1β. Mutations in NLRP3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation IL-1β production by macrophages is triggered by uric acid (monosodium urate monohydrate) crystals in the joint and surrounding tissue through activation of the NLRP3 inflammasome complex.

Elevated Interleukin-1 beta (IL-1β) and very high Interleukin-18 (IL-18) levels may imply activation of the NLRP3 inflammasome, as the NLRP3 protein regulates the activation of IL-1β and caspase-1, which in turn activates IL-18. However, this is not explicitly stated in the provided text, and therefore, no conclusion can be drawn. 2 2 2

From the Research

NLRP3 Inflammasome Activation

Elevated Interleukin-1 beta (IL-1β) and very high Interleukin-18 (IL-18) levels are associated with the activation of the NLRP3 inflammasome. The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the innate immune system, mediating caspase-1 activation and the secretion of proinflammatory cytokines IL-1β and IL-18 in response to microbial infection and cellular damage 3.

Mechanisms of Activation

The activation of the NLRP3 inflammasome is triggered by diverse stimuli, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage 3. The assembly of the NLRP3 inflammasome is initiated by the recruitment and cluster-dependent activation of caspase-1, leading to the proteolytic activation of inflammatory cytokines such as IL-1β and IL-18 4.

Association with IL-1β and IL-18

Elevated levels of IL-1β and IL-18 are indicative of NLRP3 inflammasome activation, as these cytokines are produced and secreted in response to the activation of the inflammasome 5, 4, 6. The release of IL-1β and IL-18 can aggravate tissue injury and induce hypercoagulability, favoring the progression of various diseases, including COVID-19 and cardiovascular diseases 5, 6.

Key Findings

• Elevated IL-1β and IL-18 levels are associated with NLRP3 inflammasome activation 5, 4, 6.
• The NLRP3 inflammasome is activated by diverse stimuli, including ionic flux, mitochondrial dysfunction, and lysosomal damage 3.
• The assembly of the NLRP3 inflammasome is initiated by the recruitment and cluster-dependent activation of caspase-1, leading to the proteolytic activation of IL-1β and IL-18 4.