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.

Keywords: NLRP3 inflammasome; comorbidities; pathogenic player; rheumatoid arthritis; therapeutic potential.

Figure 1

The flow diagram of the literature selection process (Search conducted on 31 October 2023). Duplicates and manuscripts with incomplete data have been excluded. RA: rheumatoid arthritis; NLRP3: nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs) containing a pyrin domain-3; ASCVD: atherosclerotic cardiovascular disease; OP: osteoporosis; ILD: interstitial lung disease.

Figure 2

The proposed model for the pathogenic role of the NLRP3 inflammasome signaling pathway in RA and its clinical implications as the therapeutic potential. Several ligands that bind to TNFRs and TLRs can activate nuclear factor (NF)-κB. As a transcription factor, activated NF-κB can translocate into the nucleus and thereby activate the expression of NLRP3 and pro-IL-1β. As an endogenous ligand, anti-citrullinated peptide antibodies (ACPA) can promote NF-κB phosphorylation through binding to TNFRs and TLRs. In the second signal, extracellular ATP can bind to P2X7 and thereby lead to K⁺ efflux and extracellular Ca⁺⁺ influx, which activate the NLRP3 inflammasome with the overproduction of the mature form of IL-1β and IL-18. The NLRP3 inflammasome activation also leads to the cleavage of gasdermin D, which promotes pyroptosis with the formation of pores in the cell membrane and the release of IL-1β and IL-18. ACPA can also activate the pannexin channel, resulting in ATP secretion and NLRP3 inflammation activation. In RA monocytes, complement C1q and pentaxin 3 (PTX3) synergistically activate the NLRP3 inflammasome and pyroptosis. Several compounds have been identified as inhibitors of the components of the NLRP3 inflammasome signaling pathway. MCC950, VX-765, osthole, and sulforaphane can inhibit the activation of the NLRP3 inflammasome. Tofacitinib, one JAKi, may restore the balance of γδTreg/γδT17 cells in RA by inhibiting the NLRP3 inflammasome. Disulfiram inhibits GSDMD and thereby blocks pyroptosis and the release of IL-1β and IL-18. Anakinra, an IL-1β receptor antagonist, blocks the effects of NLRP3 inflammasome downstream cytokine. Among natural products, both Baihu-Guizhi decoction (BHGZD) and celastrol can inhibit NLRP3 activation by blocking the NF-κB pathway. HCQ could inhibit Ca²⁺-activated K⁺ channels and then impair inflammasome activation. The microRNA-30a and miR-223 inhibit the expression of NLRP3 and inflammasome activation. Red arrows indicate activation of NLRP3 inflammasome. Block arrows trigger protein expression pathway. RA: rheumatoid arthritis; TNFα: tumor necrosis factor-α; TNFRs: TNFα receptors; TLRs: Toll-like receptors; ATP: adenosine triphosphate; PTX3: pentaxin 3; GSDMD: gasdermin D; IL: interleukin; ASCVD: atherosclerotic cardiovascular disease; OP: osteoporosis; ILD: interstitial lung disease.