ReviewSpecific inflammasomes in complex diseases
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)
Thioredoxin-interacting protein mediates ER stress-induced beta cell death through initiation of the inflammasome
Cell Metab.
(2012)IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress
Cell Metab.
(2012)NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis
Cell
(2011)Caspase-1 deficiency decreases atherosclerosis in apolipoprotein E-null mice
Can. J. Cardiol.
(2012)Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice
Biochem. Biophys. Res. Commun.
(2012)Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
Am. Heart J.
(2011)DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88
Cell
(2012)The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation
J. Neuroinflammation
(2012)- et al.
The Nlrp3 inflammasome: contributions to intestinal homeostasis
Trends Immunol.
(2011) Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges
Mucosal Immunol.
(2012)
Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease
Gastroenterology
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.
Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta
J. Biol. Chem.
The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes
Curr. Biol.
Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity
J. Invest. Dermatol.
Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1
Immunity
A coding variant in NLRP1 is associated with autoimmune Addison's disease
Hum. Immunol.
Interleukin 18 gene variation and risk of acute myocardial infarction
Cytokine
Interleukin-18 promoter polymorphisms in patients with Behcet's disease
Hum. Immunol.
NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells
Immunity
Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome
Nat. Genet.
Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition
N. Engl. J. Med.
Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1
Immunity
Inflammasome activation and IL-1beta target IL-1alpha for secretion as opposed to surface expression
Proc. Natl. Acad. Sci. U. S. A.
How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes
Br. J. Clin. Pharmacol.
Thioredoxin-interacting protein links oxidative stress to inflammasome activation
Nat. Immunol.
Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes
Nat. Immunol.
The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance
Nat. Med.
Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling
Nat. Immunol.
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.
Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity
Nature
Interferon-gamma produced by bone marrow-derived cells attenuates atherosclerotic lesion formation in LDLR-deficient mice
J. Atheroscler. Thromb.
Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene
J. Exp. Med.
NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Nature
Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome
Cell Death Dis.
Gout-associated uric acid crystals activate the NALP3 inflammasome
Nature
A pilot study of IL-1 inhibition by anakinra in acute gout
Arthritis Res. Ther.
The NALP3 inflammasome is involved in the innate immune response to amyloid-beta
Nat. Immunol.
Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis
Proc. Natl. Acad. Sci. U. S. A.
NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components
Nat. Med.
Cited by (72)
The role of IL-1β and TNF-α in intervertebral disc degeneration
2020, Biomedicine and PharmacotherapyFamily Mediterranean fever and other auto-inflammatory diseases: From genetics to medical practice
2020, Bulletin de l'Academie Nationale de MedecineNOD-like receptors and inflammasomes: A review of their canonical and non-canonical signaling pathways
2019, Archives of Biochemistry and Biophysics