From the Guidelines
Activated NLRP3 can cause autosomal dominant autoinflammatory diseases, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular (NOMID/CINCA) syndrome. These diseases are characterized by gain-of-function mutations in the NLRP3 gene, leading to excessive inflammation and tissue damage 1. The severity of the disease phenotype can range from mild to severe, with NOMID/CINCA being the most severe form.
- Key features of these diseases include:
- Recurrent episodes of fever, rash, and joint pain
- Elevated levels of inflammatory markers, such as IL-1β and IL-18
- Potential for long-term complications, such as amyloidosis and hearing loss
- Genetic testing, including next-generation sequencing (NGS), is crucial for accurate diagnosis of these conditions 1.
- Targeting the NLRP3 inflammasome with specific inhibitors may represent a promising therapeutic approach for these diseases, as blocking this pathway could potentially reduce inflammation and disease severity 1.
From the FDA Drug Label
CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Autoinflammatory Syndrome-1 [CIAS1]). 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.
Diseases caused by activated NLRP3:
- CAPS (Cryopyrin-Associated Periodic Syndromes): a group of rare genetic disorders caused by mutations in the NLRP3 gene, characterized by fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.
- Gout flares: characterized by activation of resident macrophages and infiltrating neutrophils in the joint, and concomitant overproduction of IL-1β resulting in an acute painful inflammatory response, triggered by uric acid crystals through activation of the NLRP3 inflammasome complex.
- Still’s disease: a severe autoinflammatory disease driven by innate immunity by means of proinflammatory cytokines such as IL-1β. 2 3
From the Research
Diseases Caused by Activated NLRP3
- Gout arthritis (GA) is a common disease caused by the activation of NLRP3 inflammasome, which is triggered by the deposition of monosodium urate (MSU) crystals in articular and periarticular spaces 4, 5, 6.
- Pseudogout, associated with the deposition of calcium pyrophosphate dihydrate (CPPD) crystals, is also linked to the activation of NLRP3 inflammasome 6.
- Neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders are other conditions that may be exacerbated by the dysregulation of NLRP3 inflammasome 7, 8.
Mechanisms of NLRP3 Activation
- The activation of NLRP3 inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1 4.
- Various stimuli, including ion influx, mitochondrial dysfunction, reactive oxygen species production, and lysosomal damage, can trigger the activation of NLRP3 inflammasome 7, 8.
Role of NLRP3 in Diseases
- The NLRP3 inflammasome plays a critical role in the initiation and progression of gout arthritis, and may represent a prospective diagnostic biomarker and therapeutic target 4, 5.
- The NLRP3 inflammasome is also involved in the pathogenesis of other inflammatory diseases, and its regulation may ameliorate NLRP3-mediated diseases 7, 8.