Targeting IL-1β in disease; the expanding role of NLRP3 inflammasome

doi:10.1016/j.ejim.2010.03.005

European Journal of Internal Medicine

Volume 21, Issue 3, June 2010, Pages 157-163

https://doi.org/10.1016/j.ejim.2010.03.005 Get rights and content

Abstract

NLRP3 inflammasome activation and IL-1β secretion have recently emerged as a central mechanism in the pathogenesis of disease. Genetically defined syndromes like cryopyrin-associated periodic syndromes (CAPS, cryopyrinopathies) and familial Mediterranean fever (FMF) or diseases associated with NLRP3 activation by danger signals like gout, pseudogout, Alzheimer's disease or type 2 diabetes are included in this group of diseases. The contribution of anakinra, a recombinant, nonglycosylated human IL-1 receptor antagonist, in both the identification and treatment of such syndromes was considerable. Recently, rilonacept, a long-acting IL-1 receptor fusion protein, and canakinumab, a fully humanized anti-IL-1β monoclonal antibody, have been developed, with the intention to further extent IL-1β inhibition treatment strategies to a broader spectrum of disorders beyond the characterized autoinflammatory syndromes, offering a more favorable administration profile. On the other hand, the developed caspase-1 inhibitors, even though effective in experimental models, were not proven efficient in the treatment of inflammatory diseases.

Introduction

The innate immune system is assigned to recognize and encounter bacterial and viral infections. Recently, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) have emerged as key players for the proper accomplishment of this process through recognition of pathogen associated molecular patterns or PAMPs [1]. Except from PAMPs, NLRs also sense endogenous stress signals known as damage associated molecular patterns or DAMPs [1], [2]. NLR dependent recognition of either exogenous or endogenous danger signals initiates the recruitment of adaptor proteins and the formation of molecular platforms referred to as inflammasomes [1], [2]. The subsequent activation of caspase-1 results in the post-transcriptional, proteolytic modulation of the related cytokines interleukin-1β (IL-1β), IL-18 and probably IL-33 from their precursor to their active and secreted form, enhancing the inflammatory process. Among several NLRs that form inflammasome platforms, the most studied are NALP1, NALP3 (NLRP3) and IPAF [1], [2].

Section snippets

NLRP3 inflammasome and IL-1β in disease

The identification of the critical role of NLRP3 inflammasome in the maturation of the above mentioned cytokines, motivated the study of its role in the pathogenesis of several syndromes. The term IL-1β dependent autoinflammatory syndromes has been adopted for such syndromes. This group of diseases is characterized by defective regulation of innate immune response and the absence of autoantibodies or antigen-specific T cells [3].

Dysregulation of NLRP3 inflammasome due to mutations in

Strategies for inflammasome targeting in disease

The proposed key pathogenic role for IL-1β dysregulation in the inflammatory process provided the rationale for inflammasome targeting strategies (Fig. 2). Even though both IL-1β blockade and caspase-1 inhibition have been suggested in order to inhibit the effect of inflammasome hyperactivity, IL-1β blockade strategies are used in clinical practice.

IL-1 inhibitors

Currently, the developed IL-1 inhibitors are anakinra, a recombinant IL-1Ra; rilonacept, a ‘cytokine trap’; and canakinumab, a monoclonal anti-IL-1β antibody (Table 2).

Cryopyrin-associated periodic syndromes

Three distinct but genetically and phenotypically related rare disorders caused by autosomal dominant or de novo mutations of NLRP3 are included in this group. From mild to severe, the cryopyrinopathies encompass FCAS, a disorder that presents with cold-induced fevers, urticaria-like rash and systemic inflammation; MWS, characterized by unrelated to cold exposure fever, arthritis, rash and sensorineural hearing loss that prior to treatment with IL-1β inhibitors was leading to amyloidosis in 25%

Caspase-1 inhibitors

In order to limit the biological effect of caspace-1 and the subsequent enhanced IL-1β and IL-18 maturation, small molecular inhibitors of the active site of caspase-1 have been developed. Several caspase-1 inhibitors have been used in experimental models but clinical trials were only conducted for pralnacasan (VX-740) and VX-765. Clinical trials for the use o pralnacasan in RA, psoriasis and osteoarthritis have been discontinued due to liver abnormalities observed in animal toxicology models

Concluding remarks

Dysregulation of NLRP3 inflammasome, as demonstrated for cryopyrinopathies and proposed for FMF and PAPA syndrome, or activation by endogenous or exogenous danger signals, as suggested for gout, gains a critical role in the better understanding of disease pathogenesis, offering a target for therapeutic interventions.

IL-1 inhibition consists in a novel strategy for the treatment of an increasing spectrum of diseases. It has been proven a revolutionary approach for the management of the disease

Learning points

•
NLRP3 inflammasome constitutes a high molecular complex that regulates IL-1β secretion, while it is implicated, directly or indirectly, in a wide group of disorders.
•
IL-1β dependent autoinflammatory syndromes constitute a group of disorders characterized by defects in essential inflammasome proteins or inflammasome regulatory elements.
•
IL-1 inhibitors constitute an effective and well tolerated therapeutic approach for the treatment of such syndromes.
•
Except from anakinra, a recombinant IL-1

Conflict of interest

The authors declare no financial or commercial conflict of interest.

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Review articleTargeting IL-1β in disease; the expanding role of NLRP3 inflammasome

Abstract

Introduction

Section snippets

NLRP3 inflammasome and IL-1β in disease

Strategies for inflammasome targeting in disease

IL-1 inhibitors

Cryopyrin-associated periodic syndromes

Caspase-1 inhibitors

Concluding remarks

Learning points

Conflict of interest

Immunity

Cell

Mol Cell

Lancet

Am J Kidney Dis

Joint Bone Spine

Ann Allergy Asthma Immunol

Am J Med

Function of Nod-like receptors in microbial recognition and host defense

Immunol Rev

The inflammasomes: guardians of the body

Annu Rev Immunol

Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease

Annu Rev Immunol

Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome

Nat Genet

De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases

Arthritis Rheum

The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production

Proc Natl Acad Sci USA

Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway

Proc Natl Acad Sci USA

Gout-associated uric acid crystals activate the NALP3 inflammasome

Nature

MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals

J Clin Invest

The NALP3 inflammasome is involved in the innate immune response to amyloid-beta

Nat Immunol

Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica

Science

The NLRP3 inflammasome: a sensor for metabolic danger?

Science

Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Nat Immunol

An autoinflammatory disease due to homozygous deletion of the IL1RN locus

N Engl J Med

An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist

N Engl J Med

Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade

J Exp Med

The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis

Arthritis Rheum

Determination of cytokines in synovial fluids: correlation with diagnosis and histomorphological characteristics of synovial tissue

Ann Rheum Dis

Expression and function of the NALP3 inflammasome in rheumatoid synovium

Immunology

Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)

Rheumatology (Oxford)

The genetics and immunopathogenesis of inflammatory bowel disease

Nat Rev Immunol

CARD15 mutations in Blau syndrome

Nat Gen

Nod-like proteins in immunity, inflammation and disease

Nat immunol

The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity

Arthritis Rheum

Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry

Nat Immunol

NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation

Nat Med

Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production

Nature

Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response

Eur Cytokine Netw

The role of the interleukin-1–receptor antagonist in blocking inflammation mediated by interleukin-1

N Engl J Med

Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France

Ann Rheum Dis

Review article
Targeting IL-1β in disease; the expanding role of NLRP3 inflammasome