Activation of NALP1 inflammasomes in rats with adjuvant arthritis; a novel therapeutic target of carboxyamidotriazole in a model of rheumatoid arthritis

Abstract

BACKGROUND AND PURPOSEPro-inflammatory cytokines are important in rheumatoid arthritis (RA) and their production is mainly regulated by NF-κB and inflammasomes. Carboxyamidotriazole (CAI) exhibits potent anti-inflammatory activities by decreasing cytokines. Here, we have investigated NACHT, LRR and PYD domains-containing protein (NALP) inflammasomes in a rat model of RA and explored the therapeutic effects of CAI in this model and the involvement of NF-κB and inflammasomes in the actions of CAI. EXPERIMENTAL APPROACHThe anti-arthritic effects of CAI were assessed in the adjuvant arthritis (AA) model in rats, using radiological and histological techniques. NALP1 and NALP3 inflammasomes, NF-κB pathway and pro-inflammatory cytokines levels were measured with Western blots, immunohistochemistry and ELISA. KEY RESULTSCAI decreased the arthritis index, improved radiological and histological changes, and reduced synovial IL-1β, IL-6, IL-18 and TNF-α levels in rats with AA. Compared with normal rats, the 70 kDa NALP1 isoform was up-regulated, NALP3 was down-regulated, and levels of the 165 kDa NALP1 isoform and the adaptor protein ASC were unchanged in synovial tissue from AA rats. CAI reduced the 70 kDa NALP1 isoform and restored NALP3 levels in AA rats; CAI inhibited caspase-1 activation in AA synovial tissue, but not its enzymic activity in vitro. In addition, CAI reduced expression of p65 NF-κB subunit and IκBα phosphorylation and degradation in AA rats. CONCLUSION AND IMPLICATIONSNALP1 inflammasomes were activated in synovial tissues from AA rats and appeared to be a novel therapeutic target for RA. CAI could have therapeutic value in RA by inhibiting activation of NF-κB and NALP1 inflammasomes and by decreasing pro-inflammatory cytokines.

Inflammasomes contributing to inflammation in arthritis

“…This particular polymorphism resulted in increased expression of NLRP1. In an adjuvant‐induced arthritis model in rats, increased NLRP1 expression was also observed, and inhibition of NLRP1 inflammasome ameliorated the symptoms of arthritis in AIA rats and CIA mice . The prominent role of NLRP1 inflammasome in CIA mice may explain why NLRP3 deficiency had a limited effect on arthritis induction in this animal model.…”

“…Canakinumab Anakinra Rilonacept model in rats, increased NLRP1 expression was also observed, 89 and inhibition of NLRP1 inflammasome ameliorated the symptoms of arthritis in AIA rats and CIA mice. [89][90][91] The prominent role of NLRP1 inflammasome in CIA mice may explain why NLRP3 deficiency had a limited effect on arthritis induction in this animal model. While the pathways and mechanisms leading to inflammasome activation in RA are still poorly understood, the above studies clearly show the involvement of the inflammasome platform and its downstream cytokines IL-1β and IL-18 in RA disease.…”

IL-18BP is decreased in osteoporotic women: Prevents Inflammasome mediated IL-18 activation and reduces Th17 differentiation

“…There are reports that patients with endogenous Cushing’s syndrome (CS) who have decreased bone mass and enhanced risk for osteoporotic fractures have raised levels of serum IL-18 24 . Enhanced serum levels of IL-18 are also reported in RA 25 . However, there is no direct study in post menopausal osteoporosis.…”

The MC4 receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage

“…The NOD‐like receptor (NLR) family, pyrin domain containing 1 (NLRP1) inflammasome is the first member to be characterized among the NLR family and mostly expressed in neurons and glial cells (Abulafia et al, ; Tan et al, ). The activation of NLRP1 inflammasome converts precursor caspase‐1 into cleaved caspase‐1 via proximity‐induced autoactivation (Fann, Lee, Manzanero, Chunduri, et al, ; Fann, Lee, Manzanero, Tang, et al, ; Martinon, Burns, & Tschopp, ; Tan et al, ; Zhu et al, ). Cleaved caspase‐1 further cleaves precursor IL‐1β into biologically active mature pro‐inflammatory IL‐1β (Chavarria‐Smith & Vance, ).…”