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Abstract Number: 1044

Novel Compound Cytokine Release Inhibitory Drug 3 (CRID3) Inhibits the NLRP3 Inflammasome in Rheumatoid Arthritis

Trudy McGarry1, Mary Connolly1, Rebecca C. Coll2, Avril A. B. Robertson3, Matthew A. Cooper3, Luke A. O'Neill2, Douglas J. Veale1 and Ursula Fearon1, 1Dublin Academic Medical Centre, Translational Rheumatology Research Group, Dublin, Ireland, 2Inflammation Research, School of Biochemistry and Immunology, Dublin, Ireland, 3The University of Queensland, Brisbane, Australia

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: cytokines, inflammasome activation, innate immunity, rheumatoid arthritis (RA) and toll-like receptors

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Session Information

Session Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: The NLRP3 inflammasome is a multi-protein complex activated in response to environmental pathogens. This results in caspase-1-dependant cleavage of pro-IL-1β and IL-18 to their active and mature form, induction of which leads to a variety of biological effects associated with infection, inflammation and autoimmunity. Cytokine Release Inhibitory Drug 3 (CRID3) is a novel inhibitory molecule thought to be active in the NLRP3 pathway. In this study, we examined the effects of Toll-like Receptor 2 on inflammasome activation and cytokine secretion. Furthermore, the role of CRID3 on the NLRP3 pathway in the RA joint was examined.

Methods: Rheumatoid Arthritis ex vivo synovial tissue biopsies were cultured in the presence or absence of synthetic Toll-like Receptor 2 agonist Pam3CSK4 (1 µg/mL). Expression of inflammasome component NLRP3 in addition to the pro and mature/active forms of IL-1β and IL-18 were assessed by Taqman PCR and ELISA. TLR-2-induced pro-inflammatory cytokine secretion (IL-6, IL-8, TNFα) was also assessed by ELISA. RA synovial biopsies were incubated in the presence or absence of CRID3 (100 nM), a novel inhibitory compound which is thought to act on or closely to NLRP3. Expression of NLRP3, IL-1β and IL-18 expression was analysed by Taqman PCR and ELISA. The effect of CRID3 on ex vivo pro-inflammatory cytokine secretion (IL-6, IL-8, TNFα) was also determined by ELISA.

Results: TLR2 stimulation significantly induced transcript levels of NLRP3 and pro IL-1β and IL-18 in RA ex vivo synovial tissue biopsies, a model which maintains cell-cell contact, preserves the synovial architecture and closely reflects the in vivo environment.  Additionally, protein expression of IL-1β and IL-18 was increased in comparison to basal control.  Pam3CSK4 significantly increased secretion of pro-inflammatory cytokines IL-6, IL-8 and TNFα. Incubation of synovial biopsies with CRID3 resulted in a decrease of pro IL1β, which was mirrored by a decrease in active IL-1β and NLRP3 expression. Spontaneous release of IL-6, IL-8 and TNFα were also reduced following CRID3 treatment.

Conclusion:  TLR2 signalling induces NLRP3 activation in the RA joint, resulting in the secretion of inflammasome related cytokines IL-1β and IL-18. Additionally, we show for the first time that CRID3 is a novel compound which inhibits inflammasome activity in RA, and subsequent induction of pro-inflammatory pathways.


Disclosure:

T. McGarry,
None;

M. Connolly,
None;

R. C. Coll,
None;

A. A. B. Robertson,
None;

M. A. Cooper,
None;

L. A. O’Neill,
None;

D. J. Veale,

Abbvie,

2,

MSD,

2,

Pfizer Inc,

2,

Roche ,

2,

Pfizer ,

5,

Roche ,

5,

Abbott,

8,

MSD,

8,

Pfizer,

8,

Roche ,

8;

U. Fearon,
None.

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