BRIEF REVIEW www.jasn.org The Inflammasomes in Kidney Disease Hans-Joachim Anders* and Daniel A. Muruve† *Department of Nephrology, Medizinische Poliklinik, University of Munich, Munich, Germany; and †Department of Medicine, Division of Nephrology and Hypertension and the Immunology Research Group, Institute of Infection, Immunity, and Inflammation, University of Calgary, Calgary, Alberta, Canada ABSTRACT Renal inflammation is a universal response to infectious and noninfectious triggers. DAMP signaling can also trigger inappro- Sensors of the innate immune system, such as Toll-like receptors or RIG-like priate inflammation in sterile types of in- receptors, provide danger recognition platforms on renal cells that integrate and jury and thereby contribute to unnecessary translate the diverse triggers of renal inflammation by inducing cell activation and organ damage and dysfunction. The sci- the secretion of proinflammatory cytokines and chemokines. As a new entry, the ence of danger recognition has only re- inflammasome-forming NLR genes integrate various danger signals into caspase- cently been explored in the field of ne- 1-activating platforms that regulate the processing and secretion of pro-IL-1␤ and phrology,10 and it is still unclear how pro-IL-18 into the mature and active cytokines. Accumulating data now document innate immunity translates infectious and a role for the NLRP3 inflammasome and IL-1␤/IL-18 in many diseases, including noninfectious danger into the various atherosclerosis, diabetes, amyloidosis, malaria, crystal-related diseases, and other forms of kidney disease. Here we focus on autoinflammatory disorders, identifying this innate immune pathway as an attrac- the NLR family of genes that form intracel- tive therapeutic target. Here we review the current knowledge regarding inflam- lular multiprotein proteolytic complexes masome signaling and outline existing evidence on the expression and functional termed “inflammasomes.”11–13 role of the inflammasome-caspase-1-IL-1␤/IL-18 axis in kidney disease. We further provide a perspective on the potential roles of the inflammasomes in the patho- genesis of acute and chronic kidney diseases. NLR GENES AND THE INFLAMMASOME J Am Soc Nephrol 22: 1007–1018, 2011. doi: 10.1681/ASN.2010080798 The NLR gene family consists of 22 members in humans, 35 in mice, and Cytokine expression and immune cell in- molecular patterns (PAMPs), resulting several hundreds in plants.12 NLR genes filtration causing renal inflammation ac- the engagement of nuclear factor-␬B have conserved NACHT domains that me- companies almost all kidney diseases. (NF-␬B),5 IFN regulatory factors, and diate nucleotide (ATP or GTP)-dependent Renal inflammation always involves the mitogen-activated protein kinase signal- protein oligomerization (Figure 2). Al- innate immune system, whereas antigen- ing pathways modulating proinflamma- most all members also contain a C-ter- specific (adaptive) immunity may or tory and type I IFN genes. minal leucine-rich repeat domain that may not be present. Innate immunity is a Knowledge regarding the mecha- likely functions in ligand sensing. The germline-encoded system first charac- nisms that trigger innate immunity has NLR genes can further be subdivided terized as a front line for antimicrobial de- increased exponentially during the last 2 fense. This arm of the immune system in- decades. It is now clear that the innate volves several distinct families of soluble immune system can also respond to non- Published online ahead of print. Publication date and cellular receptors that activate proin- microbial stimuli, particularly to intra- available at www.jasn.org. flammatory signaling pathways (Figure 1). cellular molecules that are released from Correspondence: Dr. Daniel A. Muruve, Department of Medicine, University of Calgary, 3330 Hospital Drive These cellular receptors include Toll-like intracellular compartments of necrotic NW, Calgary, AB, T2N 4N1 Canada. Phone: 403-220- receptors (TLRs),1–4 retinoic acid-induced cells.6–9 During infection, such damage- 2418; Fax: 403-210-3949; E-mail: [email protected]. gene-like receptors, nucleotide-binding associated molecular patterns (DAMPs) Dr. Hans-Joachim Anders, Medizinische Poliklinik, Uni- versity of Munich, Pettenkoferstr. 8a, 80336 Muenchen, domain-leucine-rich repeat (or NOD-like release from injured tissues, which alerts Germany. Phone: 49-89-51603583; Fax: 49-89- receptors; NLRs), scavenger receptors, and the immune system and provides addi- 51603379; E-mail: [email protected] C-type lectins that are activated by various tive signals to those induced by the patho- Copyright © 2011 by the American Society of bacterial and viral pathogen-associated gen load and associated PAMPs. However, Nephrology J Am Soc Nephrol 22: 1007–1018, 2011 ISSN : 1046-6673/2206-1007 1007 BRIEF REVIEW www.jasn.org PAMPs DAMPs dsds DNA RNA VIRUSES Pore-formingorming + ttoxins,oxins, AATPTP K TRAM P2X7P TIRAP TLR1/2/6 TIRAP TLR5 TIRAP TLR4 TRIF MyD88 MyD88 MyD88 MAL MAL DNA Pannexin IRF5 IRF5 VIRUSES K+ ENDOSOME DAMP/DDA effluxefflux PAPAMPAMP ssRNA CpG- influxinnflux DNA dsRNA IPAF, NLRPs, AIM2 PAMPs, TLR7/8 TLR9 TLR3 crystals MyD88 TRIF Cathepsins MDA-5 RIG-1 ASC TIRAP TIRAP ROS IRAK4 TRAF6 IRAK1 TBK1 PHAGOLYSOSOME TRAF3 TRAF3 IPS1 INFLAMMASOME MAPK NF-κB IRF1 IRF7 IRF5 IRF3 IRF7 Pro-caspase-1 Caspase-1 MITOCHONDRIA IL-1R pro-IL-1β CYTOSOL IL-18R pro-IL-18 NUCLEUS IFNAR TNFR, IL-1β IL-Rs, IL-18 α CCRs IFN- IFN-β IL-12, CCL2, CCL5, TNF, IL-6, IL-8 Figure 1. How pattern recognition receptors induce innate immunity. Complement factors, mannose binding lectin, and the pentraxins (C-reactive protein, serum amyloid P, pentraxin 3) are components of the humoral part of innate immunity. These molecules opsonize pathogens or apoptotic cells to induce phagocytosis through complement receptors or mannose receptors (not shown). Complement can also directly kill pathogens or cells by forming the membrane attack complex (not shown). Several groups of extracellular or intracellular innate pattern recognition receptors exist. TLR-1/2/4/5/6 recognize microbes at the cell surface. TLR3/7/8/9 recognize viral and bacterial nucleic acids in intracellular endosomes. All TLRs use the intracellular adaptor myeloid differentiation primary response gene (88) (MyD88) for downstream signaling, except for TLR3, which uses TIR-domain-containing adapter-inducing interferon-␤ (TRIF). TLR4 uses MyD88 and TRIF. All TLRs can induce the expression of NF-␬B-dependent genes, including most proinflammatory cytokines and chemokines. TLRs also induce the procytokines IL-1␤ and IL-18 (signal 1). These cytokines need caspase-1 activation as a second step before they can be released. Caspase-1 activation is under the control of the inflammasomes. For example, potassium efflux, lysosomal cathepsin leakage in the cytosol, or oxidative stress can trigger the NLRP3 inflammasome that includes the adaptor ASC and caspase 1. Type I IFNs represent a separate class of antiviral cytokines. Release of type I IFNs is strongest upon recognition of viral nucleic acids via TLR3/7/8/9 in endosomes or via cytosolic RNA and DNA receptors. The latter signal via the mitochondrial adaptor interferon promotor stimulator 1, but all pathways finally activate the transcription factors IRF3/7 for expression of the type I IFNs. All cytokine classes amplify innate immunity by interacting with their respective cytokine receptors, as shown at the bottom of the figure. All inflammasome-related cytokines ligate their receptors to trigger MyD88-dependent signaling. based on the presence of CARD activating platforms termed inflam- peptidoglycans and contribute to Crohn’s (caspase recruitment domain), PYD masomes. As an example, the best charac- disease.14–17 (pyrin domain), and acidic transactivation terized NLRs are NOD1 and NOD2 The NLRP (nucleotide-binding oli- or baculovirus inhibitory N-terminal do- (NLRC1 and NLRC2, in which “NLRC” gomerization domain, leucine-rich re- mains.11 As a group, the NLRs primarily indicates a NLR containing a CARD) that peat and pyrin, domain containing) sub- activate NF-␬B signaling or form caspase- activate NF-␬B in response to bacterial family includes 14 proteins that are 1008 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 1007–1018, 2011 www.jasn.org BRIEF REVIEW numerous cellular substrates including PYD NACHTLRR CARD NLRP1 (1473 aa) the cytokines IL-1␤ and IL-18.18,19 The generation of mature IL-1␤ and IL-18 NLRP2 (1062 aa) involves two separate processes: the in- ␬ NLRP3 (1036 aa) duction of NF- B-dependent mRNA expression and translation of a procy- NLRP4 (944 aa) tokine (signal 1) followed by cleavage of the procytokine and release of ma- NLRP5 (1200 aa) ture and active cytokine (signal 2).13,20 Only the latter depends directly on the NLRP6 (892 aa) inflammasome (Figure 1). In the case of IL-1␤, caspase-1 cleaves NLRP7 (980 aa) the 35-kD pro-IL-1␤ to the mature and secreted form of the 17-kD cytokine. NLRP8 (1048 aa) Other enzymes can also cleave these pro- cytokines in caspase-1-deficient mice NLRP9 (991 aa) (e.g., caspase-4, -5; caspase-11, -12 in NLRP10 (655 aa) mice-11, and -12 in mice; chymotrypsin; chymase; granzyme; elastase; plasmin; or NLRP11 (1033 aa) proteinase-3), but the functional rele- vance of these enzymes for IL-1␤/IL-18 NLRP12 (1061 aa) secretion is unclear.21,22 Caspase-1 has more than 40 other cellular substrates.18 NLRP13 (1043 aa) In addition to processing cytokines, in- flammasomes mediate an inflamma- NLRP14 (1093 aa) tory form of cell death termed “pyrop- tosis” and may also be involved in CARD NACHTT LRR NLRC4 (1024 aa) cellular processes such as glycoly- sis.18,23 Pyroptosis was only recently described in macrophages and consists PYD HIN200 AIM2 (343 aa) of programmed cell death involving loss of membrane integrity, unlike ap- ␤ PYD CARD ASC (195 aa) optosis, in association with IL-1 and IL-18 secretion.23,24 Because they were discovered fairly CARD p20 p10 Caspase 1 (404 aa) recently, our knowledge about the biol- ogy of the NLRP proteins and the inflam- Figure 2.