Elsevier

Clinical Immunology

Volume 147, Issue 3, June 2013, Pages 223-228
Clinical Immunology

Review
Specific inflammasomes in complex diseases

https://doi.org/10.1016/j.clim.2012.12.006Get rights and content

Abstract

Blocking the cytokines Interleukin-1beta (IL-1β) and Interleukin-18 (IL-18) benefits a diverse range of inflammatory pathologies. In each of these diseases, different cytoplasmic innate immune receptors nucleate individual protein complexes known as inflammasomes, to regulate the production of active IL-1β or IL-18. This review will outline the complex diseases where these cytokines are pathogenic, and explain which inflammasome(s) may be responsible. For example, inflammasomes nucleated by NLRP3 and NLRP6 integrate signals from metabolic and commensal systems contributing to metabolic dysfunction and type 2 diabetes. On the other hand, NLRP1 and AIM2 are more broadly implicated in autoimmunity and allergy. Furthermore, each inflammasome has unique roles in pathogen recognition, which may determine the outcome of polymicrobial infection and link different infectious co-morbidities to chronic inflammatory disease. We can now imagine a time when targeted inflammasome inhibitors will be employed in the clinic, tailoring treatments to particular diseases, and perhaps individual patients.

Highlights

► In complex diseases, multiple inflammasomes can be activated. ► Different inflammasomes contribute to different aspects of the same disease. ► Specific inflammasome inhibitors will be targeted to certain complex diseases. ► Inflammasomes balance inflammation alongside pathogenic/non-pathogenic microbiota.

Introduction

The role of the inflammasome is displayed nowhere more prominently than for patients with activating mutations in the innate immune receptor NLRP3 [1]. Different mutations result in a spectrum of disease, which can result in a profoundly debilitating systemic inflammatory state. Biochemically, activated NLRP3 engages the adaptor protein ASC to dimerise the enzyme Caspase-1, which cleaves IL-1β producing an active cytokine that is secreted from the cell. Clinically remarkable remission can be achieved by blocking IL-1β [2], although the inflammasome can also cleave and activate IL-18, and indirectly facilitate the production of IL-1α [3], [4]. Other reviews in this issue describe that disease in more detail, and the growing list of other Mendelian diseases where genetic lesions in different inflammasome pathways can cause autoinflammation. The purpose of this review is to broaden that discussion to more complex diseases where IL-1β or IL-18 is known to play a role, but as generated by one of a number of different inflammasomes in the context of additional genetic and environmental influences (Table 1). Our hope is that these initial observations point towards a future in which we delineate the role for individual inflammasomes in many more common, complex diseases, for which specific inflammasome inhibitors will then be beneficial.

Section snippets

NLRP3 and NLRP6 in obesity and diabetes

The role of IL-1 in type 2 diabetes has been well reviewed in other journals recently [5]. We now turn our attention to the inflammasome complexes that may be responsible for this pathology due to IL-1β. The first data implicating an NLR in this process came from the Tschopp lab [6]. This publication showed that NLRP3 knockout mice fed a high fat diet for 8 weeks are more glucose tolerant than wild-type, and have accelerated clearance of glucose after challenge with insulin. However it was also

IL-1 or IL-18 responsive diseases where the inflammasome activated is not yet known

There is still much work to be done. In particular, there are a number of diseases where we already know there is a striking biological response to IL-1 blockade, and yet no information exists to suggest which inflammasome might generate the active cytokine. Two examples of this are systemic onset juvenile idiopathic arthritis (SJIA) [66] and Behcet's disease [67]. For SJIA it is tempting to speculate that NLRP3 might be involved, due to the somewhat similar phenotype of patients with

Conclusion

So this is clearly a very preliminary list of inflammasomes that regulate only some of the IL-1β or IL-18 pathology in a range of complex diseases. Needless to say this list is likely to increase, as is the number of diseases themselves, where we are yet to discover the importance of inflammasome derived cytokines. Furthermore there has yet been little discussion about the role multiple inflammasomes play in the complex interplay of infectious diseases. Many fatal infections are polymicrobial

Conflict of interest

The author declares that there are no conflicts of interest.

References (80)

  • T. Kanai

    Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease

    Gastroenterology

    (2001)
  • J.A. Lust

    Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component

    Mayo Clin. Proc.

    (2009)
  • M. Okamoto

    Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta

    J. Biol. Chem.

    (2010)
  • L. Feldmeyer

    The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes

    Curr. Biol.

    (2007)
  • H. Watanabe

    Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity

    J. Invest. Dermatol.

    (2007)
  • F.S. Sutterwala

    Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1

    Immunity

    (2006)
  • M. Zurawek

    A coding variant in NLRP1 is associated with autoimmune Addison's disease

    Hum. Immunol.

    (2010)
  • W. Koch

    Interleukin 18 gene variation and risk of acute myocardial infarction

    Cytokine

    (2011)
  • Y.J. Lee

    Interleukin-18 promoter polymorphisms in patients with Behcet's disease

    Hum. Immunol.

    (2006)
  • S.L. Masters

    NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells

    Immunity

    (2012)
  • H.M. Hoffman

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

    Nat. Genet.

    (2001)
  • R. Goldbach-Mansky

    Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition

    N. Engl. J. Med.

    (2006)
  • O. Gross

    Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1

    Immunity

    (2012)
  • A. Fettelschoss

    Inflammasome activation and IL-1beta target IL-1alpha for secretion as opposed to surface expression

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • M. Boni-Schnetzler et al.

    How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes

    Br. J. Clin. Pharmacol.

    (2012)
  • R. Zhou

    Thioredoxin-interacting protein links oxidative stress to inflammasome activation

    Nat. Immunol.

    (2010)
  • S.L. Masters

    Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes

    Nat. Immunol.

    (2010)
  • B. Vandanmagsar

    The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance

    Nat. Med.

    (2011)
  • H. Wen

    Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling

    Nat. Immunol.

    (2011)
  • S. Normand

    Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • J. Henao-Mejia

    Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

    Nature

    (2012)
  • T. Niwa

    Interferon-gamma produced by bone marrow-derived cells attenuates atherosclerotic lesion formation in LDLR-deficient mice

    J. Atheroscler. Thromb.

    (2004)
  • M.J. Nicklin

    Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene

    J. Exp. Med.

    (2000)
  • P. Duewell

    NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

    Nature

    (2010)
  • P. Menu

    Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome

    Cell Death Dis.

    (2011)
  • F. Martinon

    Gout-associated uric acid crystals activate the NALP3 inflammasome

    Nature

    (2006)
  • A. So

    A pilot study of IL-1 inhibition by anakinra in acute gout

    Arthritis Res. Ther.

    (2007)
  • A. Halle

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

    Nat. Immunol.

    (2008)
  • F. Meissner et al.

    Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • S.L. Doyle

    NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components

    Nat. Med.

    (2012)
  • Cited by (72)

    View all citing articles on Scopus
    View full text