The Expanded Role of the Inflammasome in Human Disease

The next major discovery in this field involved crystal-induced disease with the demonstration that monosodium urate as well as calcium pyrophosphate crystals can activate macrophages to produce IL-1b via the NLRP3 inflammasome.¹¹ The link with gouty inflammation was obvious. Again, a proof-of-concept study using IL-1Ra as inhibitor showed remarkable effects in acute gout,¹² the second disease to be linked to inflammasome activation. The third and most recent disease to demonstrate a role for Inflammasome-mediated IL-1b release is diabetes mellitus, where, in fact, a clinical study showing the therapeutic effect of IL-1 inhibition preceded the biochemical studies demonstrating the role of the NLRP3 inflammasome.^13-14 In mice that are deficient for components of the NLRP3 inflammasome, the diabetic phenotype is attenuated.

The expanding list of inflammasome activators now include silica and asbestos fibers, vaccine adjuvants such as alum, cells undergoing necrosis, and the contact sensitizer trinitrochlorobenzene (TNCB) (see Table 1, p. 18).^15-20 These findings will require confirmatory studies in the human disease setting but suggest that the inflammasome may be involved in myriad disease-associated inflammatory processes.

Important unresolved questions for now relate to what promotes the inflammasome to assemble and how it senses danger signals. Although the NLR component possesses a sensor domain in its LRR region, there is no proof that it makes direct contact with the activating agent. Indeed, there is evidence for a multitude of intermediate cellular changes that link cellular contact with the activator and assembly of the inflammasome complex. Current theories for this process invoke a role for cell stress and the generation of reaction oxygen species, the redox protein thioredoxin binding protein, as well as potassium flux and extracellular ATP acting via the P2X7 receptor.^14,21 Identification of the pathway(s) and their cell specificity will be of enormous interest, because they may give further insights into potential targets for drug development as well as disease mechanisms.

Figure 3: Tophaceous deposits on the thumb of a patient with cardiomyopathy, renal failure, and hyperuricemia who has recurrent attacks of polyarticular gout.

A Future for Anti–IL-1 Therapy?

The description of the inflammasome and its role in IL-1b processing has coincided with an expanding application of IL-1 blockade in disease. The discovery of NLRP3 mutations in CAPS patients made IL-1 an obvious target for therapeutic intervention, and the concept has been validated by studies using different IL-1 inhibitors. The results of blocking IL-1 were spectacular in a disease that had hitherto been extremely difficult to manage and had considerable morbidity as well as mortality (see Figures 3 and 4, below right). To date, three molecules have been tested in clinic: IL-1Ra or anakinra, IL-1 Trap or rilonacept, and the anti–IL-1b monoclonal antibody canakinumab. All three agents are highly effective in treating the spectrum of CAPS manifestations in pilot studies as well as in controlled studies, and the treatments were well tolerated.^10,22,23