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Home , AIM2, GSDMD, IL1A, Interleukin, Interleukin 18, Pyroptosis

BRIEF REVIEW www.jasn.org

Of Inflammasomes and Alarmins: IL-1b and IL-1a in Kidney Disease

Hans-Joachim Anders

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität, Munich, Germany

ABSTRACT Kidney injury implies danger signaling and a response by the . The enigmatic importance for the regulation inflammasome is a central danger recognition platform that triggers local and of systemic and tissue inflammation, systemic inflammation. In immune cells, inflammasome activation causes the release pro- and anti-inflammatory factors bal- of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, indepen- ance the system at all levels, i.e., the re- dently of the inflammasome. Both IL-1a and IL-1b ligatethesameIL-1receptor ceptor ligands, the transmembrane cell (IL-1R) that is present on nearly all cells inside and outside the kidney, further am- surface receptors, and the signaling plifying and release. Thus, the inflammasome-IL-1a/IL-b-IL-1R pathways (Figure 1).4,5 system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflam- IL-1a mation. This review gives an overview of arising concepts of inflammasome and IL-1a is constitutively present in kerati- IL-1a/b regulation in renal cells and in experimental kidney disease models. There nocytes and other epithelia including is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL- tubular epithelial cells, whereas macro- 1R system, ranging from recently described small molecule inhibitors of NLRP3, a phages, , endothelial cells, component of the inflammasome complex, to regulatory agency–approved IL-1– fibroblasts, and mesangial cells express neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the IL-1a precursor only upon acti- the potential therapeutic benefits of using such compounds to block the inflamma- vation.5 The 31 kDa IL-1a precursor some-IL-1a/IL-b-IL-1R system in kidney disease should be further explored. lacks a fragment and is already biologically as active as the pro- J Am Soc Nephrol 27: 2564–2575, 2016. doi: 10.1681/ASN.2016020177 cessed 18 kDa “mature” form.6 Therefore, cells constitutively expressing IL-1a were considered “aloadedgun” that can at any time release a proinflammatory alarmin The immune system has a central role in extends the discussion to the alarmin upon cell .6–8 This way necrotic a maintaining and in regain- IL-1 . A comprehensive view on the ex- cells alert surrounding tissues and set up ing homeostasis after injury. Infectious pression and biologic effects of the in- local tissue inflammation. and noninfectious triggers of injury have flammasome-IL-1 axis in renal cells fl an identical capacity to initiate in am- and its functional contribution to experi- IL-1b mation, e.g., a gouty or bacterial arthritis mental and human kidney disease is IL-1b is not constitutively expressed and both present as clinically indistinguish- required to appreciate the potential of in- its secretion is largely restricted to circu- fl fl – able acute joint in ammation. In the last ammasome-IL-1 related drugs in this lating that are activated for 15 years the research community has un- evolving area of translational nephrology. raveled the molecular mechanisms of danger signaling but this area remains a UPDATE ON IL-1 BIOLOGY Published online ahead of print. Publication date source of unexpected discoveries. Nu- available at www.jasn.org. merous data have accumulated since the Journal of the American Society of Since its first cloning in 1984 the knowl- Correspondence: Dr. Hans-Joachim Anders, Medi- fi zinische Klinik und Poliklinik IV, Klinikum der Universität Nephrology published a rst overview edge on the biology of the IL-1 family of München, Ziemssenstr.1, 80336 Munich, Germany. about inflammasomes in kidney disease has expanded to considerable Email: [email protected] 1 in 2011. This brief review provides an complexity as reviewed elsewhere in de- Copyright © 2016 by the American Society of – update on inflammasome biology and tail (Figure 1).2 4 As the system is of Nephrology

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Figure 1. The families of IL-1 cytokines and cytokine receptors activate innate and adaptive immunity. Activated or dying cells re- lease all sorts of cytokines of the IL-1 family that specifically interact with several transmembrane surface receptors present on most cell types of the body. Some induce cell activation (IL-1R, IL-18R, IL-36R), others inhibit cell activation (IL-33R, TIGIRR, SIGIRR). This way the family elicits numerous regulatory effects on renal cells, immune cells of the innate and , either activating or inhibiting their respective cell type–specific functions. AG, antigen; G-CSF, colony-stimulating factor; MФ,; NETs, extracellular traps; NK cell, ; TIR domain, Toll/-1 (TIR) domain. enzymatic cleavage of the inactive 266 infiltrating and neutro- to activate -driven pro–IL-1a precursor into the 153 amino phils can release large amounts of IL- processing.10 Necrotic cells release both acid mature form of IL-1b.5 Therefore, 1b, whereas parenchymal cells may the 31 and 18 kDa forms of IL-1a pas- IL-1b mainly contributes to systemic in- release only small amounts under cer- sively from intracellular stores to alarm flammation by initiating acute phase tain circumstances.4 surrounding cells.6 In those cells that response in the liver such as coexpress IL-1a and IL-1b,IL-1a secretion C-reactive , by activating endo- Enzymatic Processing can also be inflammasome-dependent, thelial cells, by triggering , by caus- Pro–IL-1a is a substrate for the calcium- implying that IL-1a and IL-1b are re- ing neutrophil mobilization from the dependent, nonlysosomal cysteine pro- leased together.12 (leukocytosis), and by tease calpain (Figure 2),5,10,11 but little is Pro–IL-1b is a true precursor that activating all classes of leukocytes and known about how external triggers reg- requires enzymatic processing for renal cells (Figure 1).9 Within tissues, ulate calpain activity. Calcium release activation. Extrinsic or intrinsic dan- mainly resident dendritic cells and from intracellular stores seems sufficient ger signals that initiate the canonical

J Am Soc Nephrol 27: 2564–2575, 2016 Inflammasome-IL-1 Axis in Kidney Disease 2565 BRIEF REVIEW www.jasn.org

specklike protein (ASC), and -1 (Figure 2).15 Different inflammasomes are defined by the different NLRs that serve as sensors for intracellular danger signals.15 Whereas the NLRC4, NLRP6, -7, -12, or AIM2 inflammasomes recog- nize preferably -associated mo- lecular patterns (PAMPs), NLRP1 and NLRP3 are more promiscuous and have the capacity to translate a large variety of different cytosolic danger signals into the caspase-1–dependent secretion of IL-1b.15 Many of these may also occur during kid- ney injury, such as mitochondrial release of reactive oxygen species and pore form- ing toxins, ATP, or osmotic pressure that affect intracellular potassium and calcium concentrations.15–17 Other danger-associated molecular patterns (DAMPs) that contribute to NLRP3- driven renal inflammation include uromodulin particles,18 biglycan,19 extracellular histones,20 oxalate, or urate crystals that destabilize lysosomes for cathepsin leakage into the like other phagocytosed microparticles.21–23 Cytosolic LPS is a known trigger for noncanonical inflammasome signaling involving caspase-11 in mice and - 4 and -5 in humans.24–27 Caspase-11/4/5 activation leads to cleavage of the cyto- Figure 2. Inflammasome activation in dendritic cells and macrophages involves nu- solic protein gasdermin,24,28 and gasder- merous elements. Dendritic cells first need to induce the expression of the inflammasome min’sN–terminally cleaved product p70 components and of pro–IL-1a and pro–IL-1b.Thiscanoccurvia cytokine receptors or Toll-like subsequently activates the NLRP3 in- receptors (TLRs). Activation of inflammasome assembly can occur upon numerous intracellular flammasome for caspase-1–dependent danger signals such as mitochondrial reactive oxygen species release, lysosomal pro–IL-1b processing.24 leakage, and potassium efflux or calcium influx. The multiprotein inflammasome complex – b Unlike macrophages, dendritic cells forms a wheel-like structure to trigger caspase-1 driven IL-1 (and IL-18) enzymatic activation. – b fl fi do not constitutively express pro IL-1 In ammasome brils grow in size to a single macromolecular complex called ASC speck. fl Calcium activates calpain, which cleaves pro–IL-1a to IL-1a, but in contrast to pro–IL-1b,IL-1a and the in ammasome components. fi is already biologically active, and hence an alarmin. IL-1a,IL-1b, and IL-18 together with other Dendritic cells rst require a priming NF-kB–dependent cytokines and activate cytokine and chemokine receptors in signal via Toll-like receptors or cytokine an autocrine, paracrine, or systemic manner. Noncanonical inflammasome signaling, e.g., receptors that induce NF-ĸB–dependent triggered by cytosolic LPS, involves caspase-11 (mice) and caspase 4/5 (humans), which cleave transcription of NLRP3, ASC, caspase-1, gasdermin D. The cleaving product activates NLRP3. Noncanonical inflammasome signaling pro–IL-1a, and IL-1b.15 It is of note that is a recognized trigger for , an immunogenic form of cell that leads to the also other enzymes have been found to release of numerous intracellular components that have the capacity to activate a plethora of cleave pro–IL-1b, such as serine prote- fl pattern recognition receptors and close the vicious cycle of necroin ammation. CCL, CC ases in neutrophil granules.29 chemokine ; CCR, CC-chemokine receptor. The activation of the NLRP3 inflam- masome is tightly regulated.30 A20- inflammasome–dependent activation of cells, and metalloendopeptidase meprin A driven ubiquitination of NLRP3, PYRIN caspase-1 have been extensively studied in in epithelial cells.5,14 Inflammasomes are domain-only protein POP1-dependent mononuclear phagocytes.13 In other im- cytosolic wheel-like complexes composed inhibition of inflammasome assembly, mune cells other may activate by the assembly of NACHT, LRR and or reactive oxygen species–driven sup- IL-1b, e.g., proteinase-3 in , PYD domains-containing proteins (NLRP), pression of caspase-1 are just three such granzyme A in NK cells, chymase in mast the linker molecule -associated regulatory mechanisms.31–33

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IL-1 Receptor specks elicit DAMP-like proinflammatory albumin overload induces NLRP3 expres- IL-1R1 is expressed on nearly all cells and effects conceptually similar to crystals sion in proximal tubular cells of rats and hardly regulated.4 Its activation induces and other microparticles once they get in cultured HK-2 cells, and IL-1b release the release of the soluble IL-1 receptor phagocytosed and induce lysosomal could be demonstrated but only in cell antagonist that can neutralize the bio- leakage and activate the NLRP3 inflam- lines in vitro.59 Indeed, the roles of logic effects of IL-1a and IL-1b.9,34 masome of the phagocyte.46,47 Finally, NLRP3, ASC, and caspase-1 for canonical IL-1R2 has the same inhibitory ef- several studies suggest that NLRP3 inflammasome signaling in macrophages fect.4,35 IL-1R1 ligation signals via the and ASC have other, inflammasome- and dendritic cells are consistent in lit- adaptor protein MyD88 to the kinases independent biologic functions, such erature.21 The published data become IRAK-2 and -4 and uses TRAF6 to in- as facilitating the anti-inflammatory conflicting when reporting pro–IL-1b volve NF-ĸB, p38, , and and profibrotic effects of TGF-bR processing and IL-1b release from renal ERK for initiating the transcription of signaling.48,49 parenchymal cells.60,61 Only a few stud- inflammatory cytokines including pro– ies demonstrate the secretion of mature IL-1a and pro–IL-1b.4 IL-1b from immune cell–free tissue DATA IN RENAL CELLS: specimens or from nonimmune renal Consequences of Inflammasome EXPRESSION, RELEASE cell cultures by ELISA and western Activation or NLRP3/ASC Induction blot. Those that do, obtain inconclusive Other Than IL-1 Release Kidney injury exposes renal cells to nu- results.60–64 Convincing evidence was Inflammasome activation also induces merous inflammasome activators, such demonstrated for renal fibroblasts.65 the secretion of mature IL-18 (Figure as ATP, uric acid, histones, uromodulin, Others conclude on inflammasome ac- 1).36 IL-18 is clearly expressed by tubular oxalate or cystine crystals, and matrix tivation from immunostaining or tran- epithelial cells in addition to infiltrating degradation products.17,18,20,50–53 But script analysis,66–68 which is inadequate immune cells,37 but if the tubular ex- are the inflammasome components ex- given the post-transcriptional nature of pression of IL-18 is inflammasome- pressed at all in the kidney and, if so, do inflammasome activity. Eventually, confo- dependent or not and its contribution they contribute to canonical inflamma- cal laser microscopy might be a feasible to kidney injury remains under de- some signaling54,55?IL-1a and IL-1b are way to prove intrarenal inflammasome bate.38,39 The strong induction of IL-18 both induced by NF-ĸB signaling but still activation by documenting ASC speck for- inside the kidney upon injury has raised display heterogeneous expression patterns mation,46,69 but ASC speck complexes much attention as IL-18 could be a use- in solid organs of healthy mice.56 Espe- have not yet been reported inside the kid- ful urinary biomarker of kidney injury as cially IL-1b can be induced in tubular ep- ney. In fact, recent reports on renal cell or discussed in detail elsewhere.40 Inflam- ithelial cells in kidneys of young mice and kidney tissue NLRP3/ASC immunostain- masome activation by intracellular bac- the expression of both IL-1a and IL-1b ing depict diffuse cytoplasmic positivity teria or LPS can induce necrotic , increases with age.56 Essential elements rather than ASC specks. In addition, referred to as pyroptosis.41,42 In murine of the NLRP3 inflammasome have mean- Nlrp3/Asc2/2 control sections were not macrophagesthisprocessislargely while been found to be expressed in most used to prove specificity of immunolabel- caspase-11–dependent (caspase-4/5 renal parenchymal cell types (Table 1) ing.66–68 However, renal parenchymal in humans).24,26 Pyroptosis re-exposes but their functional roles inside the kid- cells may process pro–IL-1b into mature intracellular to extracellular ney and species-specific differences re- IL-1b via the metalloendopeptidase host defense elements and increases lo- main under debate.57–59 For example, meprin A.5,14 Data on caspase-11 and renal cal inflammation by DAMP and alarmin release including IL-1a (Figure 2).41 Whether NLRP3 agonists other than cy- Table 1. Expression and function of inflammasome components in renal tosolic LPS induce pyroptosis in cells parenchymal cells other than macrophages is still under NLRP3, ASC Speck IL-1b IL-1a debate but human immunodeficiency Component Pyroptosis depletes CD4 T cells Expression Formation Release Release 61,112 61 in a caspase-1–dependent manner.43 Endothelial cells Yes ? ?? 63 Recently,itwasshownthatSyk-and No Mesangial cells No63 ? — ? 113 Jnk-dependent Tyr144 Yes113,114 of ASC induces ASC speck aggregate Podocytes Yes61,66,95 ? Yes61,115 ?? 44 fi formation. ASC specks grow to bril- No63 No63 like macromolecular structures inside Tubular epithelial cells Yes49,59,62,76,78,116–119 ?Yes70 the cytosol that are eventually released No21,62 No71 into the extracellular space, e.g., upon ? ? 65 ? 65 pyroptosis.45,46 Such extracellular ASC ?, unknown; —, absent.

J Am Soc Nephrol 27: 2564–2575, 2016 Inflammasome-IL-1 Axis in Kidney Disease 2567 BRIEF REVIEW www.jasn.org cell pyroptosis are still sparse. Yang, et al. proposed tubule cell pyroptosis to occur upon ischemia- based on an association with caspase-11 activ- ity,70 but a functional role of caspase-11 was not proven and others did not find any effect on postischemic tubular necrosis with pan-caspase inhibitor treatment.71,72 IL-1a has potent immunostimulatory ef- fects on renal cells73 but little is known about the capacity of renal parenchymal cells to release IL-1a from intracellular stores and elicit alarmin-like effects on sur- rounding cells.6

ROLE IN ANIMAL MODELS OF KIDNEY DISEASE

AKI Models Necroinflammation occurs mainly in AKI, e.g., in infective pyelonephritis, thrombotic microangiopathy, necrotiz- ing GN, and tubular necrosis (Figure 3).74 Up to now only the latter two have been studied using mice deficient for Nlrp3, Asc, Casp1/11, Il1a,orIl1b (Table 2). Whenever tested, mutant mice were consistently protected from renal necroinflammation.21,75 However, postischemic tubular necrosis depends on NLRP376–79 but not on ASC.76 This finding could imply an additional, Figure 3. The inflammasome/IL-1 system contributes to renal necroinflammation. inflammasome-independent, biologic Necroinflammation can occur in the glomerulus (A) or the tubulointerstitial compartment effect of ASC in postischemic AKI. Stud- (B). The primary event can be intravascular NETosis, as in ANCA vasculitis, or renal cell ies performed on the model of acute ox- necrosis, such as in ischemic tubular injury. Histone, DAMP, and alarmin (IL-1a) released alosis suggest inflammasome signaling from dying cells activate the NLRP3 inflammasome (IL-1a/b release) and induce IL-1R to be restricted to intrarenal dendritic signaling, which implies local inflammation. Especially histones also kill other cells, re- cells.21 The independent contribution sulting in a crescendo of tissue inflammation and necrosis, i.e., necroinflammation. The of IL-1a to AKI has so far been addressed consequences in the glomerulus and the tubules are illustrated. Both lead to a drop out of only by Lee et al.80 Il1a-deficient mice nephrons and the clinical syndrome of AKI. were protected from cisplatin-induced AKI but, unexpectedly, markers of in- flammation were not different from by in situ immune complex formation. leukocyte infiltration.63 In fact, in 2004 wild-type control mice.80 However, not Ten years after Timoshanko et al. had Timoshanko et al. already identified in- all studies document a consistent block- demonstrated that autologous anti- filtrating leukocytes as the only source of ade of intrarenal inflammation and tu- GBM GN is attenuated in Il1b-deficient glomerular IL-1b release.85 Altogether, bular necrosis in postischemic or toxic mice,84,85 Andersen et al. identified the AKI involves canonical inflammasome– AKI in models upon blockade of the NLRP3/ASC inflammasome as the mediated IL-1b secretion mostly from IL-1 axis.81–83 These findings may imply mechanism of glomerular IL-1b the tubulointerstitial network of dendritic that IL-1 is not a universal mediator of production in this model.86 However, cells and infiltrating leukocytes as AKI and its role is context-dependent. Lichtnekert et al. could not find any part of the autoamplification loop of Models of acute glomerular injury phenotype of mice deficient for Nlrp3, necroinflammation (Figure 3). The role pose new questions. Autologous anti- Asc, and Casp1/11 with heterologous of leukocyte pyroptosis, NETosis, and GBM disease is a model of GN triggered anti-GBM GN, a model with little IL-1a in this context remains poorly

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Table 2. AKI models in Nlrp3-, Asc-, Casp1/11-, Il-1a–, and Il-b–deficient mice ous from the cryopyrin-associated Disease Model Inflammation Renal Function Reference periodic syndrome (CAPS), a group of Severe GN genetic disorders of periodic fever and fl Heterologous anti-GBM GN Nlrp32/2 ——63 multifocal tissue in ammation caused Asc2/2 ——63 by gain-of-function mutations in Casp1/112/2 ——63 the NLRP3 gene.89 Genetic variants in Autologous anti-GBM GN Nlrp32/2 ↓ Better 86 IL-1–related associate with the Asc2/2 ↓ Better 86 risk for ESRD.90,91 The pathogenic con- IL1b2/2 ↓ Better 84,85 cept of CAPS was verified by dramatic clinical responses to IL-1 inhibitors 2 2 ↓ 120 LPS-induced Casp1/11 / Better such as the IL-1b neutralizing anti- Tubular necrosis body (Ilaris), the soluble Ischemia- reperfusion Nlrp32/2 — Better 76,77,79 decoy receptor (Arcalyst), Asc2/2 ——76 Casp1/112/2 ↓ Better 121 and the recombinant human IL-1Ra 89 IL1a2/2 ↓ ? 122 (Kineret). Important for nephrologists IL1b2/2 ↓ ? 122 is renal amyloidosis secondary to CAPS Cisplatin Nlrp32/2 ——79 or any other hereditary systemic (auto-) Asc2/2 ??123 inflammatory disorder that responds Casp1/112/2 ↓ Better 118 well to therapeutic IL-1 inhibition (Table IL1a2/2- — Better 80 4).92–96 Numerous other IL-1b–,IL-1a–, Rhabdomyolysis Nlrp32/2 ↓ Better 75 or IL-1R1–specificbiologicdrugcan- 2 2 ↓ 75 Asc / Better didates and one oral caspase-1 inhib- 2 2 ↓ 75 Casp1/11 / Better itor are currently in clinical trials.7 In IL1b2/2 ↓ Better 75 2013, canakinumab was approved in Eu- Acute oxalosis Nlrp32/2 ↓ Better 21 Asc2/2 ↓ Better 21 rope for preventing remittent gouty ar- Casp1/112/2 ↓ Better 21 thritis based on its capacity to suppress fl Anti-GBM GN, anti-glomerular basement membrane GN; —,absent;↓, suppressed; ?, unknown. painful in ammation in acute gout at- tacks faster than intramuscular steroid injection.97 Unlike most other drugs studied. In ANCA vasculitis neutrophil or oxalate crystal–induced nephropathy or used in gout, canakinumab can also be serine proteases such as cathepsin G, ureter obstruction were only conducted used in patients with CKD.98 Interest- elastase, and proteinase 3 mediate intra- using Nlrp3-deficient mice, but consis- ingly, renal function seems to improve renal IL-1b processing.29 tently displayed a protected phenotype when gout is treated with IL-1 inhibi- (Table 3). Bone marrow–derived vehicle tion.99 Also, safety and pharmacoki- CKD Models cells overexpressing IL-1Ra suppress in- netics of rilonacept are not affected by Glomerular pathology drives CKD pro- terstitial inflammation in obstructive ne- CKD or even ESRD.100 Now, this finally gression in most cases, diabetic nephrop- phropathy.87 However, in nephritis allows for the testing of the old theory athy being the clinically most prevalent of C57BL/6-(Fas)lpr mice lack of NLRP3 that IL-1 induction seen in hemodialysis disease category (Figure 4). Shahzad and ASC consistently presented an aggra- patients contributes to dialysis-related et al. provided a comprehensive data vated phenotype.48 As the same was not systemic inflammation and complica- set documenting a role of the NLRP3/ found for lack of IL-1R or IL-18 an in- tions.101 A first interventional study ASC inflammasome for the progression flammasome-independent effect was pos- showed that can significantly of STZ-induced diabetic nephropathy tulated.48 For example, NLPR3 and ASC improveC-reactiveprotein,IL-6,and (Table 3).61 Their analysis also in- mediate TGFR-dependent SMAD phos- serum albumin levels in patients on he- cluded bone marrow transplant studies phorylation,48 a signaling pathway known modialysis.102 These data create hopes documenting a significant contribution to suppress lupus nephritis via the known that blocking IL-1–driven systemic in- of NLRP3-mediated caspase-1 activation immunoregulatory effects of TGF-b sig- flammation could improve nutritional inside nonimmune cells to podocyte loss, naling on .88 status and body wasting, and eventually albuminuria, and glomerulosclerosis.60,61 dampen accelerated cardiovascular dis- As their experiments involved conven- ease in ESRD.103 A trial with monoclonal tional knockout mice it remains unclear IL-1–RELATED DRUGS AND anti–IL-1b IgG in diabetic if this relates to NLRP3 in nonimmune CLINICAL DATA kidney disease is ongoing.104 Clinical tri- cells in- or outside the kidney. Reports als testing whether IL-1 blockade can on other CKD models such as hyperten- The relevance of the NLRP3 inflamma- also improve outcomes in diseases such sive nephrosclerosis, Western diet-, toxin-, some for human disease becomes obvi- as GN, vasculitis, or AKI are still awaited.

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Figure 4. The inflammasome/IL-1 system promotes CKD. CKD is devoid of tissue necrosis and currently there is little evidence for renal cell or other forms of regulated cell necrosis being involved in CKD progression. There are data supporting a role of the NLRP3 inflammasome and IL-1 in CKD but the mechanisms are unclear. Most likely systemic release of IL-1, e.g., in diabetes or systemic lupus, contributes to systemic endothelial dysfunction (ED), a process also promoting leukocyte adhesion and vascular leakage (micro- albuminuria) in the kidney. Furthermore, intrarenal inflammasome activation in immune cells, and eventually also in renal parenchymal cells, may contribute to local inflammation, cell stress, and cell loss. For example, podocyte detachment promotes albuminuria, hyper- trophy of the remaining podocytes, FSGS, and subsequently first focal-global and later diffuse glomerulosclerosis-related nephron loss. In this process the inflammasome components NLRP3 and ASC may contribute to SMAD phosphorylation downstream of TGFR signaling during epithelial-mesenchymal transition (EMT) of parietal epithelial cells (PEC), and induce extracellular matrix production by tubular epithelial cells (not depicted). Whether the same also occurs in interstitial fibroblasts is currently unknown (not depicted). A role of NLRP3 and ASC has also been reported on systemic autoimmunity where that assures the immunosuppressive effect of TGFR signaling on im- mune cells (not depicted).

Table 3. CKD models in Nlrp3-, Asc-, caspase-1/11–, Il-1a–, and Il-b–deficient cystinosis, light chain–related Fanconi mice syndrome, fibrillary GN, or crystalloglo- Renal bulinemiaareallasrareasCAPSbut Disease Model Gene Inflammation Fibrosis Reference Function secondary oxalosis-related AKI is more 105 Glomerulopathy common. Timing is probably an is- Lupus nephritis Nlrp32/2 ↑ Worse ? 48 sue, because the diagnosis of AKI, based Asc2/2 ↑ Worse ? 48 on its current definition, is not recog- Casp1/112/2 ↑ Worse ? 48 nized before the kidney is largely de- Diabetic nephropathy Nlrp32/2 ↓ Better ↓ 61 stroyed. Therefore, IL-1 blockade might Asc2/2 ↓ Better ↓ 61 be more feasible in chronic disorders for 2 2 ↓ ↓ 61 Casp1/11 / Better which some experimental evidence 2 2 ↓ ↓ 124 Toxic glomerulopathy Nlrp3 / Better exists such as primary hyperoxaluria 2 2 ↓ ↓ 125 Hypertensive nephrosclerosis Asc / ? 61,106,107 2 2 ↓ ↓ 106 or diabetes. The ongoing Western diet nephropathy Nlrp3 / ? fl Tubulopathy Canakinumab Anti-In ammatory Throm- Obstructive nephropathy Nlrp32/2 ↓/— N/A ↓/— 62,126 bosis Outcomes Study aims to evaluate b Chronic oxalosis Nlrp32/2 ↓ Better ? 107 whether IL-1 inhibition can reduce ↑, increased; ?, unknown; ↓,suppressed;—, absent; N/A, not applicable. rates of recurrent myocardial infarction, stroke, and cardiovascular death among high risk patients with persistent eleva- tions of CRP.108 PERSPECTIVES FOR TARGETING analogy to its clinical effectiveness in Several small molecule–based NLRP3 THE -IL-1 AXIS IN gout and the role of the NLRP3-IL-1 axis antagonists have been validated in KIDNEY DISEASE in crystal- and microparticle-related tis- preclinical studies. Arglabin, a sesquiterpene sue inflammation, IL-1 blockade may lactone from the Chinese herb Artemisia Which types of human kidney disease also be instrumental in crystalline ne- myriantha, can specifically inhibit cho- would be eligible for IL-1 blockade? In phropathies. Primary hyperoxaluria, lesterol crystal–induced IL-1b,butnot

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Table 4. Clinical reports and ongoing trials of IL-1 blockade in patients with presumed or manifest kidney disease Drug Disease Trial Phase NCT Identifier Reference Canakinumab CAPS-related (renal) amyloidosis Case reports 93 Gout in CKD 3 NCT01029652 97 NCT01080131 Proliferative diabetic retinopathy 1 NCT01589029 Anakinra CAPS-related (renal) amyloidosis Case reports 93 Gout in CKD 2–3 NCT02578394 Inflammation in CKD 2 NCT00420290 102 Nutrition, resistance, and inflammation in CKD 2 NCT02278562 Resistance and inflammation in CKD 2 NCT02278562 Henoch–Schönlein purpura Case report 127 Rilonacept Vascular dysfunction in CKD 2a NCT01663103 Inflammation in CKD 2a NCT00897715 Gevokizumab Type 2 diabetic kidney disease 2a EudraCT2013–003610–41 104 NCT, ClinicalTrials.gov identifier; EudraCT, European Union Clinical Trials register.

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