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The 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 , 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 , 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- -forming NLR integrate various danger signals into - 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 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 (ATP or GTP)-dependent Renal inflammation always involves the mitogen-activated 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

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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 . 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 (), 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 that are

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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. Human inflammasome-related genes. The NLRP subfamily of NLR genes masome is somewhat limited. Unlike the consists of 14 members that are typified by an N-terminal PYD in addition to conserved other families of pattern recognition re- NACHT and leucine-rich repeat domains common to all NLR genes. NLRP1 is unique ceptors that have recognizable PAMP li- in that it also carries a C-terminal CARD. NLRC4 (Ipaf1) is a member of the NLR family gands, ligands for many NLRP members with an N-terminal CARD that can directly interact with caspase-1. AIM2 is a DNA- or even their function are not yet known. interacting human interferon-inducible 200 protein with an N-terminal PYD that can form a caspase1-activating inflammasome but does not belong to the NLR family. Early studies attempted to establish the Inflammasomes also generally consist of the adaptor protein ASC and the cystine NLRP proteins and the inflammasome as protease caspase-1. sensors of microbial constituents similar to the TLR paradigm. However, more re- cent work identifies many diverse micro- defined by a conserved N-terminal PYD (Figure 3).12,13 Unlike the typical signaling bial, nonmicrobial, and even endogenous domain and common NACHT and leu- cascades downstream of many innate recep- stimuli that activate the inflammasome cine-rich repeat motifs (Figure 2). Upon tors such as the TLRs or other NLR members (Table 1). These observations put into activation, the NLRP proteins oligomerize such as NOD1/2, the inflammasome is a pro- question a ligand-specific model of inflam- through homotypic molecular interactions teolytic caspase-1-activating platform. masome activation, as is the case for the and recruit the PYD-CARD adaptor protein, Caspase-1, an inflammatory caspase, does TLRs. Rather, existing evidence supports ASC, and the protease caspase-1 to form a not play a major role in . In- the notion that the inflammasome is the protein complex termed the inflammasome stead, activated caspase-1 processes final common pathway that senses cellu-

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DAMP or PAMP tion or during noninfectious types of kidney disease. 1

THE NLRP3 INFLAMMASOME

LRR The best understood inflammasome is

T NLRP3, which is activated by various H

C stimuli and expressed primarily in 12,13 NACHT NA macrophages and dendritic cells. NLRP3 in the NLRP3 gene are linked to three autoinflammatory dis- orders that include Muckle–Wells syn- PYD drome, familial cold autoinflamma- tory syndrome, and chronic infantile neurologic cutaneous and articular PYD CARD 2 syndrome.21 Provided that microbial ASC or nonmicrobial stimuli activate NF-␬B to induce pro-IL-1␤ and IL-18 (signal 1), a diverse group of additional stimuli can act as signal 2 to activate CARD p20 p10 caspase-1 through NLRP3 (Table 1). These stimuli represent additional PAMPs and Caspase 1 DAMPs that do not match with those acti- vating TLRs. For example, cellular necrosis triggers NLRP3 activation in macro- phages by release of ATP or uric acid.25 Inflammasome The multitude of NLRP3 triggers under- scores the likely function of this inflam- 3 masome as a sensor of cellular stress or injury operating through a single com- mon pathway.26–28 For example, the ac- tivation of NLRP3 occurs after endolyso- somal stress and the activation of lysosomal proteases such as cathepsin B. In studies that involve endosomal load- Caspase 1 ing with viral or crystal aggregates such as (active) adenovirus or silica, inhibition of endo- somal maturation or lysosomal protease 4 activity is sufficient to block inflam- 29–32 proIL-1β IL-1β masome activation. A second model proIL-18 IL-18 of activation proposes that engagement of ATP-dependent P2X7 receptors results in Figure 3. Simplified model of NLRP3 structure and activation. NLRP3 is maintained in a the opening of large pannexin-1 pores in stable, repressed state at baseline (likely through interactions with SGT1 and heat shock protein the cell membrane (Figure 1). The open 90129). (1) Exposure to a DAMP or PAMP releases NLRP3, which oligomerizes via its NACHT pannexin-1 pores allow NLRP3-activating domain. (2) NLRP3 oligomerization recruits the adapter protein ASC to the complex. ASC then bacterial PAMPs into the cytoplasm, re- recruits caspase-1 via a homotypic CARD interaction to complete the formation of the inflam- sulting in inflammasome activation.33 In masome. (3) Recruitment to the inflammasome triggers caspase-1 autoprocessing and gener- ation of the active p10/20 heterodimeric enzyme. (4) Active caspase-1 cleaves pro-IL-1␤ and this model, it is also proposed that any pro-IL-18 into their active and secreted forms. toxin or enzyme capable of inducing membrane pores/openings that permit the cytosolic delivery of a bacterial PAMP can lar stress or injury. As such, the inflam- (Table 2). Therefore, it is very likely that result in the activation of the NLRP3 in- masome-caspase-1-IL-1␤/IL-18 axis is inflammasomes are also involved in re- flammasome.34 Finally, a recent paper by involved in many disease conditions nal inflammation, either during infec- Zhou and colleagues35 suggests the final

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Table 1. Selected triggers for inflammasome activation Inflammasome Mediator/Ligand Source Reference NLRP1 Bacillus anthracis lethal toxin Bacillus anthracis 41 Muramyl dipeptide Bacteria 87 NLRP3 ? Sendai virus 88 ? Adenovirus 28 ? Influenzavirus 88 ? Encephalomyocarditis virus 89 ? Candida albicans 36 ? Saccharomyces cerevisiae 36 ? Neisseria gonorrhoeae 90 ? Listeria monocytogenes 74 ? Staphylococcus aureus 74 Streptolysin O and other bacterial toxins Streptococcus pyogenes and other bacteria 34, 91, 92 ATP Dying cells 74 Reactive oxygen species Cell stress (glucose, etc.)35 Uric acid crystals Dying cells, hyperuricemia 56 Cholesterol crystals Cholesterol metabolism 60 Silica/asbestos crystals Environment 59 Skin irritants Environment 93 Alum Environment 29, 94 NLRC4 Flagellin Flagellated bacteria 39, 91 AIM2 DNA 44, 45

common pathway of NLRP3 inflam- flammasome substrates such as IL-1␤ pyroptosis.42–45 In contrast to NLRP3, masome activation is through oxidative and IL-18, but also to induce the expres- AIM2 acts as a receptor that is activated stress and thioredoxin-interacting protein sion of NLRP3 required for inflam- by DNA binding. AIM2 is involved in an- (TXNIP). In the normal state, TXNIP is masome assembly and activation.37 tiviral host defense and the response to bound to the antioxidant reductase, thi- Listeria monocytogenes and Franscicella oredoxin. After oxidative stress, TXNIP re- tularensis.46–49 The identification of leases from thioredoxin to interact with OTHER INFLAMMASOMES AIM2 is also significant for demonstrat- and activate NLRP3. Because many ing that ASC- and caspase-1-containing NLRP3-activating stimuli are associated Other proteins that are known to form inflammasomes are not restricted to the with ROS production, this represents a po- inflammasomes include the NLRs, NLR family of genes. The role of these tential unifying model. NLRP1, NLRC4 (Ipaf-1), and the human inflammasomes in nonmicrobial inflam- In addition to these models, several interferon-inducible 200 protein AIM2 mation and kidney disease is unknown. other signaling molecules and cellular (absent in melanoma-2) (Figure 2).12 Other NLRs such as NLRP2 and NLRP12 events are essential for NLRP3 inflam- NLRC4 responds to bacterial flagellin have also been shown to interact with masome activation. Kϩ efflux from the cell and bacteria containing type III/IV se- ASC and activate caspase-1 in vitro; how- is necessary for activation of the NLRP3 in- cretion systems such as Salmonella typhi- ever, the biologic significance of these flammasome regardless of the stimulus.27 murium and Pseudomonas aeruginosa.38 observations and whether these NLRs In response to certain infectious agents NLRC4 can activate caspase-1 through a form true inflammasomes is unclear.50,51 such as Candida albicans or malarial he- direct CARD-CARD interaction in the mozoin, the tyrosine kinases spleen ty- absence of the adaptor, ASC.39,40 NLRP1 rosine kinase and Lyn are also essential contains a PYD domain and a C-termi- DISEASE ENTITIES INVOLVING for optimal activation of the NLRP3 in- nal CARD domain and therefore inter- THE INFLAMMASOME-CASPASE-1- flammasome.32,36 CARD9, phosphoino- acts directly with caspase-1 and -5.22 The IL-1〉/IL-18 AXIS sitide 3-kinase, and extracellular signal- NLRP1 inflammasome is activated by regulated kinase signaling downstream Bacillus anthracis lethal toxin and the Several human autoinflammatory syn- of spleen tyrosine kinase appears neces- peptidoglycan muramyl dipeptide (Ta- dromes are directly related to variations sary not only to induce expression of ble 1).41 Finally, AIM2 is a PYD contain- in inflammasome or IL-1-related genes pro-IL-1␤ but also to exert a direct effect ing human interferon-inducible 200 (Table 2). The cryopyrin-associated pe- on ASC and caspase-1 after exposure to protein that does not belong to the NLR riodic syndromes encompass Muckle– these pathogens. Finally, recent studies family. AIM2 forms a DNA-sensing in- Wells syndrome, familial cold autoin- show that cellular priming is required flammasome with ASC and caspase-1 flammatory syndrome, and chronic not only to transcribe and translate in- that mediates cytokine processing and infantile neurologic cutaneous and ar-

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Table 2. Noninfectious diseases recently related to inflammasomes Disease Potential Mechanism IL-1 Blockade Reference Genetic syndromes FMF GOF in the pyrin gene CR 95, 96 PAPA GOF mutation in the PSTPIP1 gene CR 97, 98 FCAS GOF mutation in the NLRP3 gene CR 53, 99 MWS GOF mutation in the NLRP3 gene CR 21, 53 CINCA GOF mutation in the NLRP3 gene CR 99 DIRA LOF mutation in the IL-1Ra gene CR 55 HIDS Mevalonate kinase deficiency, ? PR/CR 100 TRAPS GOF mutation in the TNF-R1 gene PR/CR 101 FCAS2 GOF mutation in the NLRP12 gene ? 102 Idiopathic syndromes adult-onset Still syndrome ? PR/CR 103 Behçet disease ? PR/CR 104 rheumatoid arthritis ? PR 103 ankylosing spondylitis ? PR polychondritis ? PR/CR 105 Schnitzler’s syndrome ? CR 106 Sweet syndrome ? CR 107 anti-synthetase syndrome ? PR/CR 108 SLE Self DNA activating AIM2? PR 109 gout/pseudogout Crystal-induced NLRP3 activation CR 56 Alzheimer’s disease Amyloid-␤-induced NLRP3 activation ? 61 amyloidosis Amyloid-␤-induced NLRP3 activation ? 61 atherosclerosis Lipid crystal-induced NLRP3 activation ? 60 diabetes Glucose-induced NLRP3 activation PR 35 arterial hypertension GOF mutation in the NLRP3 gene ? ? 110 heart failure after myocardial infarction ROS-induced NLRP3 activation PR 111 stroke ROS-induced NLRP3 activation PR 112 CNS trauma ? PR 113 multiple sclerosis ? PR 114 Environmental diseases asbestosis Particle-induced NLRP3 activation ? 59 silicosis Particle-induced NLRP3 activation ? 29 malaria Hemozoin-induced NLRP3 activation ? 62 sunburn UV-B light-induced NLRP3 activation ? 115, 116 toxic skin disease Irritant-induced NLRP3 activation ? 93 toxic liver injury ? ? 117 toxic colon injury ? ? 118, 119 FMF, familial Mediterranean fever, GOF, gain-of-function; CR, complete remission; PR, partial remission; PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome; FCAS, familial cold autoinflammatory syndrome; MWS, Muckle–Wells syndrome; CINCA, chronic infantile neurological cutaneous and articular syndrome; DIRA, deficiency in IL-1R antagonist; LOF, loss-of-function mutation; HIDS, hyper IgD syndrome and mevalonic aciduria; TRAPS, TNF receptor- associated periodic syndrome; ROS, reactive oxygen species; COPD, chronic obstructive pulmonary disease; UV, ultraviolet. ticular syndrome and are all caused by their related symptoms upon therapy now thought to represent a central different gain-of-function mutations with IL-1 antagonists. IL-1 blockade is pathogenic mechanism of gout and in the NLRP3 gene.52–54 The deficiency also partially therapeutic in several other pseudogout.56 IL-1 antagonism immedi- of IL-1 receptor (IL-1R) antagonist hereditary or idiopathic autoinflamma- ately ameliorates the clinical symptoms syndrome is also associated with in- tory diseases, but the precise mecha- of these crystal arthropathies.57,58 In vitro creased circulating IL-1␤ levels.55 Al- nisms of direct or indirect involvement studies and studies performed in mice though none of these diseases is known of inflammasomes is yet unclear (Table also support a role of the NLRP3 inflam- to directly affect the kidney, a role for 2). Crystal-induced pathologies form an- masome in translating the recognition of NLRP3 or IL-1 signaling in renal pa- other group of diseases that are recently crystal or particle formats of silica, asbes- thology cannot be excluded. related to NLRP3-mediated IL-1␤/IL-18 tos, cholesterol, ␤-amyloid, or hemozoin The pathogenic role of IL-1 in all of secretion. Monosodium urate or calcium into IL-1␤ release and disease manifesta- the aforementioned diseases was clearly pyrophosphate dihydrate crystals acti- tions of silicosis,29,59 asbestosis,59 athero- documented by complete remissions of vate the NLRP3 inflammasome, which is sclerosis,60 Alzheimer’s disease,61 and

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malaria.32,62 It would be interesting to mRNA expression profiles of NLR genes THE ROLES OF INFLAMMASOMES know whether the same mechanism ap- in human and mouse solid organs, in- IN KIDNEY DISEASE plies to kidney diseases that are associ- cluding the kidney.65 It should be noted ated with crystals or microparticles such that except for NLRP2 and NLRP10, the Inflammasomes and the Biology of as nephrolithiasis, renal amyloidosis, human kidney expresses much lower Chronic Kidney Disease The inflammasome likely plays a role cholesterol embolism, urate nephropa- mRNA levels of most inflammasome-re- in chronic kidney disease. Inflam- thy, cast nephropathy, or rhabdomyoly- lated molecules as compared with the masome-regulated cytokines such as sis. Production of reactive oxygen species human spleen. In contrast, kidneys from 6 IL-1␤ and IL-18 are implicated in ani- is another stimulus for NLRP3 activation week-old C57BL/6 mice express much mal models or human forms of chronic during hypoxia or hyperglycemia.35,63 higher levels of most NLR genes compared kidney disease (Table 3). First, IL-1␤ Interestingly, IL-1 blockade also im- with the spleen, with the exception of neu- and IL-18 induce mesenchymal mark- proves diabetes by increasing insulin se- ronal apoptosis inhibitory protein and ers in tubular epithelial cells in a dose- cretion, most likely by promoting ␤ cell NLRP3 (Figure 4). Although these data il- dependent manner.67,68 In humans, survival.64 lustrate species-specific differences in in- IL-18 and caspase-1 are expressed in Together, beyond signaling infec- flammasome expression under healthy renal tubular epithelium and patients tion, inflammasome-mediated IL-1␤/ conditions, it is well known that inflam- with chronic kidney disease or the ne- IL-18 secretion is involved in several dif- masome-related genes can be strongly in- phrotic syndrome exhibit elevated lev- ferent noninfectious diseases, suggesting duced by proinflammatory cytokines or els of IL-18.69–72 Similarly, IL-18 neu- that inflammasomes generally convey TLR agonists.12 Which cells express func- tralization prevents renal injury and cell stress to the immune system. tional inflammasomes in the kidney is fibrosis after unilateral ureteric ob- largely unknown. Several studies docu- struction (UUO) in mice.73 RENAL NLR GENE EXPRESSION ment the potential of tubular epithelial Renal tubular cell injury occurs as a re- cells to secrete IL-1␤ and IL-1866; hence, sult of various insults, including ische- Little is known of the expression of in- they should harbor all necessary elements mia, obstruction, and immune-mediated flammasome-related genes in renal cells of the inflammasome-caspase-1-IL-1␤/ mechanisms that result in the release of en- or in kidney diseases. Figure 4 illustrates IL-18 axis. dogenous cellular components capable of

0.03 0.5

0.4 0.02 0.3

0.2 0.01 0.1

mRNAGAPDH mRNA mRNAGAPDH 0 mRNA mRNAGAPDH 0 Spleen1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Spleen1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Kidney0.4 0.4 0.5 0.5 1.1 2.0 0.3 0.3 1.8 0.6 Kidney2.6 3.0 3.8 0.7 0.0 1.0 0.7 1.0 1.6 7.6 0.6Brain 0.3 0.3 0.8 1.1 2.5 2.7 1.9 0.9 1.0 0.0Brain 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 0.6Lung0.5 0.6 0.4 1.1 1.3 1.2 1.7 1.0 1.4 0.3Lung0.2 0.1 0.2 0.3 0.3 0.4 0.3 0.4 0.2 0.5Liver 0.3 0.2 0.5 1.4 1.3 0.1 1.0 1.1 0.7 0.0Liver 0.0 0.0 0.1 0.0 0.0 0.0 2.1 0.1 0.1 Heart1.4 0.5 0.3 0.5 1.5 0.8 0.3 0.2 0.4 0.3 Heart0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.7 0.0 Small intestine0.4 0.4 0.1 0.2 0.5 0.4 0.1 0.4 3.1 0.2 Small intestine0.1 0.2 1.7 2.0 0.1 0.2 0.0 1.1 0.6 0.2 Colon0.3 0.2 0.1 0.2 0.4 0.4 0.1 0.1 1.4 0.4 Colon6.3 nd 0.0 nd 0.7 19 0.0 59 37 24 Testis0.5 0.3 0.2 2.9 0.7 4.2 2.6 0.1 2.0 1.0 Testis0.4 0.5 0.0 0.4 0.1 0.7 0.1 0.5 1.5 0.7 Muscle1.9 1.3 0.6 1.2 1.5 2.3 0.4 0.6 2.8 1.9 Muscle0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

NIAP NIAP NOD1 NOD2 NOD4 NLRP1 NLRP2 NLRP3 NLRP6 NOD1 NOD2 NOD4 NLRP1 NLRP2 NLRP3 NLRP6 NLRP10 NLRP12 NLRP10 NLRP12

Figure 4. mRNA expression of inflammasome-related molecules in solid organs of humans and mice. The left panel illustrates quantitative real-time PCR performed on prenormalized cDNAs derived from poly(A)-selected DNase-treated RNAs purified from pools of healthy human tissues. The right panel illustrates respective data from cDNAs of adult C57BL/6 mice. All expression data were normalized to the respective glyceraldehydes 3-phosphate dehydrogenase (GADPH) mRNA level. Spleen mRNA expression levels are shown on top of the table. The table displays relative expression levels to the respective expression level of each transcript in spleen. Red color shades indicate higher and green shades indicate lower mRNA levels as compared with the respective mRNA levels in spleen. For example, note that mouse kidney (relative to mouse spleen) expresses much higher mRNA levels for most of the inflammasome- related genes as compared with human kidney (relative to human spleen).

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Table 3. Renal disease phenotype of knockout versus wild-type mice ؊/؊ ؊/؊ ؊/؊ ؊/؊ ؊/؊ ؊/؊ Model IL-1R IL-18 Caspase 1 NLRP3 ASC P2X7 IL-1Ra IC-GN (aNSN) 2 120 2 121 ????? IC-GN (MRL/lpr) ? 2 122 ????2 123 IC-GN (BSA) ? 2 124 ????? IgAN (ddY) ? ? ? ? ? ? 2 125 Acute kidney injury % 126 2 127 2 63,84 2 63 2 63 ? % 127 (postischemic) Interstitial fibrosis (UUO) ? 2 73 ? 2 79 ? 2 78 2 128 IC-GN, immune complex glomerulonephritis; aNSN, autologous nephrotoxic serum nephritis; MRL/lpr, mouse MRL lymphoproliferation strain; BSA, bovine serum albumin-induced glomerulonephritis; ?, unknown; IgAN, IgA nephropathy; postischemic, ischemia-reperfusion injury.

activating the NLRP3 inflammasome.54 Inflammasomes and the Biology of and nonmicrobial diseases. Acute and Many DAMPs released during renal injury Acute Kidney Injury chronic kidney disease involve the re- are capable of activating the NLRP3 in- Acute tubular necrosis (ATN) is the most lease and generation of factors such as flammasome, including reactive oxygen common cause of acute renal injury. Acute reactive oxygen species, ATP, uric acid, species, extracellular ATP, uric acid, nu- tubular injury that results in ATN can be and cholesterol crystals that correlate cleic acids, and extracellular matrix com- induced by nonmicrobial stimuli such as with disease severity and also activate ponents such as hyaluronan and bigly- ischemia-reperfusion during hypotension/ these pathways. Future studies need to can.28,35,56,74–76 This premise has been shock and toxins such as drugs or radio- address the potential role of NLR and confirmed in studies using the UUO graphic contrast. ATN is associated with an inflammasome signaling in renal cells model of chronic progressive kidney inflammatory response that includes and in animal disease models. Respec- disease in mice.77 ATP in the mito- monocyte/macrophage and neutrophil re- tive knockout mice for many inflam- chondrial fraction of necrotic cells ac- cruitment to the kidney, which is detri- masome-related proteins are available tivates the NLRP3 inflammasome mental and worsens renal injury.80,81 The for this purpose. Studies using human 25,63,74 through P2X7 receptors. Consis- data supporting the role of the inflam- renal biopsies will be useful to deter- Ϫ/Ϫ tent with these data, P2X7 mice ex- masome in acute kidney disease are strong. mine the spatial and temporal expres- hibit less tubular injury and reduced Numerous studies in humans and animal sion of inflammasome components in- inflammation and fibrosis after UUO models of acute renal disease show elevated side of the kidney and to correlate these compared with wild-type mice.78 levels of IL-1␤ and/or IL-18. These models findings with disease activity or prog- In addition to ATP, other cellular include ischemia/reperfusion injury, tox- nosis. Gene polymorphism studies on factors also activate the NLRP3 inflam- in-induced (cisplatin) tubular injury in ro- suitable patient cohorts could help to masome and play a role in chronic kid- dents,82–85 and in urine bioprofiles of crit- determine the functional significance ney disease, including the extracellular ically ill patients with ATN.86 The role of of human expression data. Finally, matrix components biglycan, hyaluro- the inflammasome in acute renal failure is IL-1R antagonist or anti-IL-1 antibodies nan.75,76 In the case of biglycan, mice further strengthened by the finding that are approved drugs that might be tested, deficient in this extracellular matrix caspase-1-deficient mice are more resistant off-label, for their potential to modulate protein are resistant to injury after to various types of acute tubular injury, in- kidney disease, which would represent UUO.76 Recent studies from our group cludingcisplatinandischemia-inducedacute the ultimate proof of significance of the confirm a role for the NLRP3 inflam- renal failure.82,84 Recently, Iyer and col- inflammasome-caspase-1-IL-1␤/18 axis masome in chronic kidney disease. leagues63 confirmed a role for the NLRP3 in- in kidney disease. This approach may not Markers of inflammasome activation flammasome and ASC in acute ischemia/ only offer a potentially fruitful area of re- (including IL-1␤, IL-18, and caspase-1 reperfusion kidney injury in mice. The search, but it will also hopefully lead to processing) are increased over a 14- activation of the NLRP3 inflammasome by novel and specific therapies for patients day time course in mice after UUO. necrotic cells is secondary to the extracellular with kidney disease. Compared with wild-type controls, matrix components biglycan and hyaluro- In conclusion, NLRs and inflam- NLRP3Ϫ/Ϫ mice exhibit a reduction in nan and mitochondrial ATP acting through masomes form a unique class of pat- tubular injury and inflammation in P2X7 receptors. tern recognition molecules that inte- this model.79 Furthermore, in a cohort grate multiple bacterial, viral, and of renal biopsies from patients with endogenous danger signals into the im- nondiabetic kidney disease, levels of FUTURE PERSPECTIVE AND mediate secretion of IL-1␤ and IL-18. mRNA encoding NLRP3 correlate with DIRECTIONS FOR RESEARCH As such, inflammasomes represent renal function, strongly suggesting that proximal and complementary ele- NLRP3 contributes to the pathogenesis The NLRs and the inflammasomes are ments of innate immune activation be- of chronic kidney disease.79 emerging as mediators of microbial cause subsequent IL-1R signaling

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