Inflammasome and Its Therapeutic Targeting in Rheumatoid Arthritis

Abstract

Inflammasome is a cytoplasmic multiprotein complex that facilitates the clearance of exogenous microorganisms or the recognition of endogenous danger signals, which is critically involved in innate inflammatory response. Excessive or abnormal activation of inflammasomes has been shown to contribute to the development of various diseases including autoimmune diseases, neurodegenerative changes, and cancers. Rheumatoid arthritis (RA) is a chronic and complex autoimmune disease, in which inflammasome activation plays a pivotal role in immune dysregulation and joint inflammation. This review summarizes recent findings on inflammasome activation and its effector mechanisms in the pathogenesis of RA and potential development of therapeutic targeting of inflammasome for the immunotherapy of RA.

Targeting inflammasome-dependent mechanisms as an emerging pharmacological approach for osteoarthritis therapy

“…The role of inflammasomes in the most common arthritic diseases, for instance, rheumatoid arthritis (RA), Gout, and juvenile idiopathic arthritis (JIA) has been described in detail in several reviews pinpointing how understanding their pathogenic mechanisms can lead to the development of novel therapeutic options. 29 , 30 , 31

Figure 1 Schematic overview of the NLRP3 inflammasome complex Inflammasomes are multi-protein complexes formed by the oligomerization of distinct domains. NLRP3 inflammasomes have an LRR domain at the C-terminus, a NACHT domain in the middle, and a PYD domain at the N-terminus.

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Research progress on rheumatoid arthritis-associated depression

“…These psychological challenges stimulate the overproduction of inflammasome in myeloid cells, which mediates responses to non-pathogenic or "sterile" stressors and leads to the development of a variety of disorders, including depression (Miller and Raison, 2016). In previous studies, the activation of inflammasome also plays a crucial role in immune dysregulation and joint inflammation (Jiang et al, 2022). NLRP3 inflammasome expression in the synovium is increased in collagen-induced arthritis (CIA) model, and targeted inhibition of NLRP3 activation, contributes to inhibiting the progression of RA (Zhang et al, 2016;Liu P. et al, 2020).…”

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

“…Damaged/dysfunctional mitochondria could release damage-associated molecular patterns (DAMPs, also known as alarmins) such as mtROS and also mtDNA. DAMPs can act through modulating innate immunity via redox sensitive inflammatory pathways (i.e., NF-κB or AP-1) or direct activation of the inflammasomes, cytosolic receptors that once activated induce the maturation of the pro-inflammatory cytokines IL-1β and IL-18 through caspase-1 activation [ 47 , 48 , 129 ]. NLRP3 is one of the most extensively described inflammasome receptors for its relevant role in the pathogenesis of many sterile inflammatory diseases such as RA.…”

“…Remarkably, it has been observed how a genetic modification that predisposes to the development of arthritis in mice results in greater activation of the NLRP3 inflammasome complex and likewise, the deletion of a functional NLRP3 complex produces notable improvements in the disease [ 168 ]. In this line, Guo C. et al have recently shown an increased expression of NLRP3, caspase-1 and IL-1β in the synovial tissue of mice in which arthritis was induced, and which was reduced by treating animals with the selective inhibitor of NLRP3, MCC950 [ 48 ]; however, phase II clinical trials in RA where inhibitor MCC950 was used were interrupted because of its hepatoxicity [ 129 ]. By contrast, caspase-1 mediated IL-18 activation in neutrophils promotes the activity of RA in a NLRP3 inflammasome independent manner [ 169 ].…”