From the Guidelines
Elevated levels of IL-1β and very high IL-18 strongly suggest NLRP3 inflammasome activation. The NLRP3 inflammasome is a protein complex that, when activated, triggers the production of these specific pro-inflammatory cytokines. IL-1β and IL-18 are both processed into their active forms by caspase-1, which is activated by the NLRP3 inflammasome. This pattern is particularly indicative of NLRP3 activation because this inflammasome is a major processor of both cytokines, with IL-18 being somewhat more specific to this pathway, as supported by the recent EULAR/PReS recommendations for the diagnosis and management of Still's disease, which highlights the importance of measuring serum IL-18 levels in the diagnosis of this condition 1.
Key Points to Consider
- The NLRP3 inflammasome plays a crucial role in the activation of pro-inflammatory cytokines, including IL-1β and IL-18.
- Elevated levels of IL-1β and very high IL-18 are indicative of NLRP3 inflammasome activation, but other inflammasomes can also contribute to their production.
- Clinical context is essential in determining the underlying cause of NLRP3 activation, as it can be associated with various conditions, including autoinflammatory disorders, metabolic diseases, and certain infections.
- Measuring other inflammasome-related markers, such as ASC specks or caspase-1 activity, can provide further confirmation of NLRP3 activation, as noted in the recent EULAR/PReS recommendations for the diagnosis and management of Still's disease, which emphasizes the need for a better understanding of the pathogenic pathways underlying this condition 1.
Implications for Diagnosis and Management
- The diagnosis of Still's disease, which is characterized by elevated levels of IL-1β and IL-18, should be considered in patients presenting with symptoms such as fever, rash, and musculoskeletal involvement.
- The measurement of serum IL-18 levels can support the diagnosis of Still's disease, as recommended by the EULAR/PReS guidelines 1.
- The management of Still's disease should involve the use of IL-1 and IL-6 inhibitors, which have been shown to be effective in reducing disease activity and improving outcomes, as noted in the recent EULAR/PReS recommendations 1.
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 key mediator of IL-1 family cytokine production, including IL-1β and IL-18 2, 3, 4, 5, 6.
Mechanisms of NLRP3 Activation
The NLRP3 inflammasome is activated by various endogenous danger signals, such as oxidized low-density lipoprotein and cholesterol crystals, which trigger the recruitment and cluster-dependent activation of caspase-1 and the subsequent proteolytic activation of inflammatory cytokines like IL-1β and IL-18 2, 4, 6.
Role of IL-1β and IL-18 in NLRP3 Activation
IL-1β and IL-18 are pro-inflammatory cytokines that play a crucial role in the inflammatory response driven by the NLRP3 inflammasome. Elevated levels of these cytokines are indicative of NLRP3 inflammasome activation, which contributes to the development and progression of various diseases, including atherosclerosis, cardiovascular diseases, and neurodegenerative diseases 3, 4, 5.
Key Findings
- The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of pro-inflammatory cytokines IL-1β and IL-18 6.
- Elevated IL-1β and IL-18 levels are associated with NLRP3 inflammasome activation, which contributes to the development and progression of various diseases 2, 3, 4, 5.
- Therapeutic strategies targeting the NLRP3 inflammasome and IL-1 cytokines are being evaluated for their effectiveness in treating diseases associated with NLRP3 inflammasome activation 3, 4, 5.