IL-1 Blockade in Autoinflammatory Syndromes

Abstract

Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)–regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular “molecular sensor” that forms a multimolecular platform, the NLRP3 inflammasome, which links “danger recognition” to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL-1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor–associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still’s, Behcet’s, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.

Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes

“…Intense research is currently being devoted to the discovery of chemical inhibitors of the NLRP3 infl ammasome ( 23 ), blocking agents of the IL-1 ␤ signaling such as IL-1R (IL-1 receptor) antagonist ( 24 ), and neutralizing antibodies ( 25,26 ). Although, there is growing evidence that nutrition is a critical modulator of the infl ammasome, few attempts have been made to inhibit the NLRP3 infl ammasome through diet.…”

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

“…systemic inflammation. Hearing loss is characteristic of NOMID and MWS, but is rarely observed in FCAS (11,12). Thus, some individuals and families segregate atypical phenotypes with overlapping features, although the phenotypes appear to breed true within families.…”

The inflammasome as a target for pain therapy

“…Furthermore, the IL-1 inhibitors anakinra, rilonacept, and canacinumab targeting IL-1 are not specific to NALP inflammasome activity and cause general immune suppression. 148 A therapeutic approach involving the targeting of inflammasome subtypes in specific diseases may be superior to the currently used antibody-based therapies, by avoiding universal suppression of IL-1 activation by other inflammasome-forming NLRs. Unfortunately, no specific inhibitor is available clinically; although both endogenous and synthetic inflammasome inhibitors have been described, this would be a big obstacle for taming the inflammasome via targeted manipulation of the inflammasome complex using a specific inhibitor.…”