Can an activated NLRP3 (Nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3) inflammasome cause sarcoidosis?

From the Guidelines

Activated NLRP3 inflammasome can contribute to sarcoidosis development, as it triggers production of pro-inflammatory cytokines, leading to persistent inflammation and granuloma formation in multiple organs. The relationship between activated NLRP3 inflammasome and sarcoidosis is complex, involving the innate immune system and the production of pro-inflammatory cytokines like IL-1β and IL-18 1. In sarcoidosis, there is evidence of increased NLRP3 activation in affected tissues, particularly in the granulomas characteristic of the disease. This excessive inflammasome activity leads to persistent inflammation and granuloma formation in multiple organs, especially the lungs and lymph nodes.

Key Points

• The dysregulation of NLRP3 appears to be part of the complex immunological cascade in sarcoidosis, where genetic susceptibility combined with environmental triggers results in an exaggerated immune response 1.
• While NLRP3 is not the sole cause of sarcoidosis, its hyperactivation represents an important pathogenic mechanism.
• The management of sarcoidosis can be challenging, and the outcome of the disease is variable, with some patients having a very good outcome and never requiring treatment, while less than 10% of patients die, mostly from advanced lung disease 1.
• The evidence for effectiveness of treatment, especially to improve quality of life (QoL), is relatively weak, and more information is needed before we can be confident about the impact of treatment on QoL 1.

Treatment Considerations

• Standard treatments currently focus on corticosteroids and other immunosuppressants rather than specific NLRP3 inhibitors.
• The majority of studies regarding treatment of symptomatic sarcoidosis have focused on pulmonary disease, with several studies evaluating other manifestations such as skin, heart, and neurologic disease 1.

From the Research

NLRP3 Inflammasome and Sarcoidosis

• The NLRP3 inflammasome pathway is activated in sarcoidosis and involved in granuloma formation, as evidenced by the expression of activated NLRP3 inflammasome components, including cleaved caspase-1 and IL-1β in lung granuloma 2.
• The activation of the NLRP3 inflammasome leads to the release of inflammatory interleukin (IL)-1β, which plays a key role in the formation of granulomas in sarcoidosis 2.
• Studies have shown that NLRP3 knockout mice have decreased granuloma formation, while miR-223 knockout mice have increased granuloma formation, suggesting that the NLRP3 inflammasome is involved in the pathogenesis of sarcoidosis 2.

Role of NLRP3 Inflammasome in Disease

• The NLRP3 inflammasome is a key player in the regulation of inflammation and has been implicated in various inflammatory diseases, including sarcoidosis 3.
• The activation of the NLRP3 inflammasome can be triggered by a variety of stimuli, including ion influx, mitochondrial dysfunction, reactive oxygen species production, and lysosomal damage 3.
• The NLRP3 inflammasome has been shown to play a pathogenic role in various inflammatory pathologies, and its inhibition has been proposed as a potential therapeutic strategy for the treatment of these diseases 3.

Treatment of Sarcoidosis

• Corticosteroids are the first-line treatment for sarcoidosis, but they can have significant side effects, and alternative treatments are often needed 4, 5, 6.
• Second-line and third-line treatments, including methotrexate, azathioprine, and TNF-α blockers, have been shown to be effective in some patients with sarcoidosis, but more research is needed to determine their optimal use 5, 6.
• The NLRP3 inflammasome has been proposed as a potential therapeutic target for the treatment of sarcoidosis, and inhibitors of the NLRP3 inflammasome, such as MCC950, have been shown to reduce granuloma formation in animal models of the disease 2.