Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses

Abstract

The discovery of the genetic causes of a rare group of immune-mediated inflammatory conditions that mimic infections and allergic conditions in their clinical presentation and the molecular understanding of the function of the mutated molecules in these diseases has led to a revolution in our understanding of the pathogenesis of systemic and local inflammation. The proteins mutated in a number of these so-called autoinflammatory diseases are part of, or regulate the activity of, intracellular molecular complexes, the inflammasomes, that sense "danger" to the body and coordinate an initial immune response. Our understanding of specific triggers of the inflammasomes, coupled with the recognition that inflammasomes are critical for activation of the proinflammatory cytokine IL-1, has provided a rational and very effective target in the treatment of a number of these rare autoinflammatory diseases. In addition, the ongoing discovery of the role of inflammasomes and IL-1 activation and secretion in a number of genetically complex disorders have fundamentally changed our view of disease pathogenesis in a growing number of disorders that were heretofore not even thought of as "immunologic" diseases.

FIG 1

The NALP3 (NLRP3) inflammasome and IL-1β–activating platform. The NALP3 (NLRP3) inflammasome is a macromolecular complex that cleaves pro–IL-1β to its biologically active form by bringing 2 molecules of pro–caspase-1 in close apposition with one another. NALP3/NLRP3, also known as cryopyrin, is comprised of an N-terminal pyrin domain (PYD), a NACHT domain, and a C-terminal leucine-rich repeat (LRR). The PYD of NALP3/NLRP3 binds the N-terminal PYD of the adaptor protein ASC (apoptosis-associated speck-like protein with a caspase recruitment domain) by homotypic interactions. The C-terminal caspase recruitment domain (CARD) of ASC binds the N-terminal CARD of pro–caspase-1, again through homotypic interactions. The NACHT domain of NALP3/NLRP3 binds the N-terminal FIIND domain (domain with function to find) of Cardinal. The C-terminal CARD of Cardinal recruits a second molecule of pro–caspase-1 to the complex. With induced proximity, the 2 pro–caspase-1 molecules undergo autocatalysis, liberating 2 catalytically active p20 and 2 catalytically active p10 domains, which form a heterotetramer capable of cleaving pro–IL-1β.

FIG 2

IL-1 receptor signaling. IL-1α and IL-1β can bind to the IL-1R1 receptor, which recruits the accessory receptor (IL-1ACP). This receptor complex forms a signaling unit. However, binding of the IL-1Ra to the IL-1R1 receptor inhibits IL-1 binding and does not allow for association with the accessory receptor, and therefore no signaling through the receptor occurs.

FIG 3

Clinical manifestations of NOMID/CINCA and DIRA. A through D, Clinical images of NOMID. Fig 3, A, shows an urticaria-like rash in a patient with NOMID. Fig 3, B, demonstrates the characteristic bony proliferation within the growth plate, as indicated by red arrows. Fig 3, C, indicates cochlear enhancement in a patient with NOMID pretreatment. Fig 3, D, shows resolution of cochlear enhancement (cochleitis) in the same patient after 3 months’ treatment with anakinra. E through G, Clinical images of DIRA. Fig 3, E, shows a pustular rash on the neck, arm, and trunk. Fig 3, F, shows heterotopic bone formation and periosteal elevation on the proximal femurs bilaterally (red arrows). Fig 3, G, shows pathognomonic widening of multiple anterior ribs in a neonate with DIRA (red arrowheads).