Background The assembly of a molecular scaffold termed the NLRP3-inflammasome complex, in monocytes, macrophages and dendritic cells, leads to the cleavage of pro-interleukin-1β(pro-IL-1β) into active IL-1β, a proinflammatory cytokine involved in innate immune responses (1). Overactivity of the NLRP3 inflammasome, leading to excessive IL-1βrelease, is involved in several autoinflammatory diseases, from cryopyrin-associated periodic syndromes (CAPS) to gouty arthritis (2).
Objectives To characterize the expression of the NLRP3-inflammasome components at the transcriptional level, in peripheral blood mononuclear cells (PBMCs) of patients with active RA undergoing treatment with infliximab (IFX).
Methods All RA patients included (n=31) were diagnosed according to the 1987 ACR criteriaand selected for IFX therapy because of a high disease activity (DAS28 ≥5.1), despite conventional DMARD treatment. Peripheral blood was obtained at the time of starting IFX (baseline), and again at week 14 of treatment. The DAS28 response at week 14 was recorded according to EULAR criteria, and also as the relative change from baseline. Blood samples were also obtained from 22 age- and sex-matched healthy controls (HCs). Total RNA was extracted from PBMCs and prepared for qRT-PCR: the relative expression of ASC, pyrin, NLRP3 FL (full-length isoform) and SL (short-length) and caspase-1 transcripts were assessed. Statistical analyses were performed using non-parametric Wilcoxon and Mann-Whitney tests, for paired and unpaired samples respectively.
Results At baseline, the transcriptional levels of ASC, pyrin, NLRP3 FL, NLRP3 SL, and caspase-1 were higher in PBMCs of RA patients than in HCs (p=0.0324, 0.0244, 0.0028, 0.0002 and 0.0168 respectively). By comparing transcript levels between baseline and week 14, we identified two groups of patients, one with upregulation of ASC (n=14) and the other with downregulation of ASC (n=10); the relative improvement in DAS28 was significantly higher in the latter group (p=0.0092). No correlations were found between response to IFX and changes in levels of the other transcripts.
Conclusions NLRP3-inflammasome-related transcripts in PBMCs were upregulated in active RA prior to receiving biologics therapy. Clinical response in patients undergoing IFX therapy may be partially explained by downregulation of ASC, for which a role independent of the NLRP3-inflammasome has recently been reported (3).
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Ippagunta SK, et al. The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization. Nat Immunol 2011; 12: 1010-6.
Disclosure of Interest None Declared
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