What is the connection between cytoplasmic Deoxyribonucleic acid (DNA) and Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18)?

From the Guidelines

Cytoplasmic DNA is connected to Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) through the activation of the inflammasome, a multiprotein platform that involves the adaptor protein ASC and NOD-like receptors (NLRs) or the cytosolic DNA sensor absent in melanoma 2 (AIM2) 1.

Key Points

• The activation of the inflammasome leads to the proteolytic maturation and release of IL-1β and IL-18, which are proinflammatory cytokines that play a crucial role in the immune response.
• IL-18 is also involved in the pathogenesis of macrophage activation syndrome (MAS), a severe and potentially fatal complication of Still's disease, and has been identified as a novel diagnostic biomarker for MAS 1.
• The connection between cytoplasmic DNA and IL-1β and IL-18 is supported by studies that have shown that elevated levels of IL-18 are associated with an increased risk of developing MAS in patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) 1.

Mechanism of Action

• The inflammasome is activated by the presence of cytoplasmic DNA, which triggers the activation of caspase-1 and the subsequent release of IL-1β and IL-18.
• IL-1β and IL-18 then act on their respective receptors to induce a proinflammatory response, which can lead to the development of MAS and other inflammatory conditions.

Clinical Implications

• The connection between cytoplasmic DNA and IL-1β and IL-18 has important implications for the diagnosis and treatment of Still's disease and MAS.
• Measurement of IL-18 levels may be useful in identifying patients at risk of developing MAS, and targeting the inflammasome may be a potential therapeutic strategy for the treatment of MAS and other inflammatory conditions.

From the Research

Connection between Cytoplasmic DNA and IL-1β and IL-18

• The connection between cytoplasmic DNA and Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) is related to the regulation of the production of active IL-1β and IL-18 through inflammasomes, which are protein complexes that nucleate in response to cytoplasmic DNA and other stimuli 2.
• Inflammasomes, such as NLRP3 and NLRP6, integrate signals from metabolic and commensal systems, contributing to metabolic dysfunction and type 2 diabetes, and are implicated in the production of IL-1β and IL-18 2.
• The production of IL-1β and IL-18 is also regulated by different inflammatory signals, with IL-18 being constitutively expressed and increased in response to stimulation of TLRs, while IL-1β is induced but not sustained after chronic treatment 3.
• IL-18 and IL-1β are processed by caspase 1 to their active forms and bind to their specific receptors, leading to the activation of NF-kB and the induction of inflammatory mediators 4, 5.
• The secretion of IL-1β and IL-18 from immune cells occurs through unconventional pathways, which can operate in the absence of complete cell lysis and cell death, and is dependent on membrane permeability 6.

Role of Inflammasomes in Regulating IL-1β and IL-18

• Inflammasomes play a crucial role in regulating the production of IL-1β and IL-18 in response to cytoplasmic DNA and other stimuli 2, 5.
• Different inflammasomes, such as NLRP1 and AIM2, are implicated in autoimmunity and allergy, and have unique roles in pathogen recognition, which may determine the outcome of polymicrobial infection and link different infectious co-morbidities to chronic inflammatory disease 2.
• The regulation of IL-1β and IL-18 production by inflammasomes is complex and involves the integration of signals from multiple sources, including metabolic and commensal systems 2, 3.

Implications for Disease Pathogenesis

• The dysregulation of IL-1β and IL-18 production has been implicated in various diseases, including inflammatory, metabolic, and infectious diseases 2, 4, 5.
• The specific role of IL-18 in the pathogenesis of hemophagocytic syndromes (HS) and other diseases, such as systemic juvenile idiopathic arthritis and adult-onset Still's disease, has been established, and IL-18BP has been used as a treatment for these conditions 4.