Inflammasome Activation and Rheumatic Disease: Six Basic Points

Article

The Nod-like receptor (NLR) family of proteins recognizes danger signals within cells, and clearly plays a role in hereditary fever syndromes. Is it also implicated in more prevalent autoinflammatory rheumatic disorders?

The Nod-like receptor (NLR) family of proteins plays a vital role in the recognition of a wide spectrum of microbial components and danger signals (e.g urate crystals) found within the cytoplasm of cells of the myeloid lineage in particular (i.e monocytes, macrophages, splenic neutrophils and dendritic cells).1 The NLRs comprise a large group of intracellular pattern- recognition receptors (PRRs) of the innate immune system. 2

A subset of the NLR network, the NLRP3 inflammasome (also known as the caspase-1 inflammasome), is a major intracellular complex involved in the production of IL-1β and IL-18.

Its activation by stimuli such as K+ flux, ATP, and/or reactive oxygen species results in cleavage of pro-IL-1β into biologically active IL-1β, mediated by caspase-1. Excessive activation of the NLRP3 inflammasome may cause autoinflammatory disorders, a spectrum of conditions caused by aberrant, immune-mediated inflammation against self, mediated through innate and adaptive immunity.3

The hereditary periodic fevers are a classic example of autoinflammatory disorders involving the NLR network. Is it also implicated in other rheumatic disorders? Research to investigate this question, including our own, is under way.4

The following are some of the most important facts regarding NLRP3-inflammasome function for practicing rheumatologists.   

1.  A role for the NLRP3 inflammasome in recurrent and chronic inflammation was initially described in a group of rare autoinflammatory conditions, termed cryopyrin-associated periodic syndromes (CAPS).6 Subsequently, the NLRP3 inflammasome has been implicated in many common diseases, including cancer, gout and diabetes.6

2. In the resting state, NLRP3 expression in innate immune cells is low.Activation requires transcription of NLRP3, which may be induced by signals such as lipopolysaccharide (LPS), tumor necrosis factor (TNF) and IL-1β.7 NLRP3 expression is not induced in lymphoid subsets and eosinophils. The NLRP3 inflammasome senses damage-associated molecular pathogens (DAMPs); subsequent secretion of IL-1β and IL-18 may be destructive to tissues, and may also play an important role in bone resorption and cartilage destruction in rheumatoid arthritis (RA).

3. The role of NLRP3 in the pathogenesis of CAPS is established and much is currently known about its activation; mutations in the NACHT domain lead to excessive IL-1β release. Considerably less is known about its role in autoimmune diseases such as RA, despite the multitude of effects IL-1b and IL-18 may have on shaping adaptive immunity.

4. There are at least 5 different protein components integral to the NLRP3 complex, including NLRP3 itself, caspase recruitment domain-containing protein 8 (CARD8), pyrin, ASC and pro-caspase-1.7 We have studied  the contribution of NLRP3 inflammasome components in active RA and the effects of anti-TNF therapy on this large intracellular complex.4 We analyzed relative gene expression of NLRP3-inflammasome components in the peripheral blood mononucleated cells (PBMCs) of 29 patients with RA who were receiving infliximab. In addition, we genotyped 1278 Caucasian RA patients from the UK-based Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort who were receiving TNF antagonists (infliximab, adalimumab and etanercept) for 34 simple genetic markers, known as single nucleotide polymorphisms (SNPs), spanning the NLRP3 gene. 

We tested for specific genetic associations between of these SNP markers and susceptibility and treatment response (DAS28 and EULAR improvement criteria) at baseline in this very large BRAGGSS cohort. In addition, we followed the 29 patients with RA on infliximab to the 14 weeks time point, at which time we were able to assess the medium-term effects of this therapy on NLRP3 inflammasome.

5.   Activity of the NLRP3 inflammasome appears to be increased in patients with active RA. Expression of 5 NLRP3-inflammasome-related genes (ASC, MEFV, NLRP3-FL, NLRP3-SL, and CASP1) in PBMCs was upregulated in active RA at baseline prior to receiving TNF blockade (but was not significantly modulated by infliximab therapy at 14 weeks).

6.  Genotypes are weakly associated with both RA disease susceptibility and response to anti-TNF therapy, suggesting that genetic variation in different components of this complex (NLRP3 and CARD8) may influence response to anti-TNF therapy in RA. As our study was large (1278 RA patients), it had sufficient power to detect effects of reasonable size, so the fact that no associations reach a level of significance suggests that the effect of any individual SNP must be small. Further work is therefore required to confirm these associations and to unravel the functional variants of the NLRP3 inflammasome complex that are driving the observed association with RA and the response to TNF blockade.

A recent analysis of synovial tissue samples from two RA cohorts of 49 and 20 patients, using a combination of global gene expression (microarray hybridization), histologic, and cellular analyses showed that patients with the myeloid phenotype of RA (which reflects the innate immune response and of which NLRP3 inflammasome is a key component) exhibited the most robust response to anti-TNF medications.8,9  Allied to our study, these recent discoveries suggest that, in the future, defining the underlying molecular and cellular phenotype in RA patients prior to therapy will have a significant impact on clinical outcome for different biological therapies.

This also highlights the need to for a better understanding of the role of inflammasomes in autoimmune diseases in general.

 

References:

1.  Guarda G, Zenger M, Yazdi AS, et al. Differential expression of NLRP3 among hematopoietic cells.J Immunol  2011 186:2529-2534

2.  Mathews RJ, Sprakes M, Hamlin PJ, McDermott MF. NOD-like receptors (NLRs) and inflammation. Arthritis Res Ther 2008 10:228

3.  McGonagle D, McDermott MF. A Proposed Classification of the Immunological Diseases.   PLoSMed  2006  3:e297

4.  Mathews RJ, Robinson JI, Battellino M et al.  Evidence of NLRP3 inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3 inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment.  Ann Rheum Dis 2014 73:1202-1210 

5.  Hoffman HM, Mueller JL, Broide DH, et al.  Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 2001 29:301-305

6.  Cook GP, Savic S, Wittmann M, et al. The NLRP3 inflammasome, a target for therapy in diverse disease statesEur J Immunol  2010 40:631-634

7.  Bauernfeind F, Ablasser A, Bartok E. Inflammasomes: current understanding and open questions. Cell Mol Life Sci  2011 68:765–83

8.  Coulthard LR, Geiler J, Mathews RJ, et al. Differential effects of infliximab on absolute circulating blood leukocyte counts of innate immune cells in early and late rheumatoid arthritis patients.  Clin Exp Immunol  2012 170:36-46

9.  Dennis G, Holweg CT, Kummerfeld SK, et al. Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arth Res Ther 2014 16:R90  

Related Videos
© 2024 MJH Life Sciences

All rights reserved.