The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

Crosstalk between Inflammation and Atherosclerosis in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Is There a Common Basis?

“…Inflammasome Nod-Like Receptor Protein 3 (NLRP3) is an important component of innate immunity, known to be involved in the pathogenesis of atherosclerosis, metabolic syndrome, diabetes, obesity, and inflammatory and autoimmune diseases. The NLRP3 inflammasome is becoming increasingly important in the pathogenesis of RA and its comorbidities, such as atherosclerotic cardiovascular disease, pulmonary interstitial disease and osteoporosis [ 83 ].…”

“…Even though the inflammasome seems to be an optimal target to treat autoimmune diseases and reduce associated CV, drugs that target the NLRP3 inflammatory pathway can have serious adverse effects, such as an increased risk of infection (anakinra, canakinumab and tofacitinib) [ 83 ].…”

Evaluating Single-Nucleotide Polymorphisms in Inflammasome Proteins and Serum Levels of IL-18 and IL-1β in Kidney Interstitial Damage in Anti-Neutrophilic Cytoplasmic Antibody-Associated Vasculitis

“…The effector cytokines of the inflammasome pathway, IL-18, and IL-1β, trigger the release of other cytokines such as IL-1α, IL-6, and tumor necrosis factor (TNF)-α, among other factors that control proliferation and the phenotype of immune cells [ 2 ]. Aberrant inflammasome assembly and activation, which has been associated with the presence of certain single-nucleotide polymorphisms (SNPs) in inflammasome genes, may contribute to the development of autoimmune diseases, such as rheumatoid arthritis [ 3 , 4 ], systemic lupus erythematosus [ 5 ], or systemic sclerosis [ 6 ].…”