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Necroinflammation in Kidney Disease

† Shrikant R. Mulay,* Andreas Linkermann, and Hans-Joachim Anders*

*Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; and †Clinic for Nephrology and Hypertension, Christian-Albrechts-University Kiel, Kiel, Germany

ABSTRACT The bidirectional causality between kidney injury and inflammation remains an area of the plasma membrane) and inflam- of unexpected discoveries. The last decade unraveled the molecular mechanisms of mation (defined by release, sterile inflammation, which established danger signaling via pattern recognition increased vascular permeability, and re- receptors as a new concept of kidney injury–related inflammation. In contrast, re- cruitment of immune effector cells).10 nal cell necrosis remained considered a passive process executed either by the The autoamplification loop of necroin- complement-related membrane attack complex, exotoxins, or cytotoxic T cells. Ac- flammation is accelerated by immunity- cumulating data now suggest that renal cell necrosis is a genetically determined and related cellular necrosis and necrosis-related regulated process involving specific outside-in signaling pathways. These findings immune activation. Necroinflammation support a unifying theory in which kidney injury and inflammation are reciprocally can be initiated by a few necrotic cells enhanced in an autoamplification loop, referred to here as necroinflammation. This that activate the , integrated concept is of potential clinical importance because it offers numerous which subsequently leads to necrosis of innovative molecular targets for limiting kidney injury by blocking cell death, inflam- more cells triggering more inflammation mation, or both. Here, the contribution of necroinflammation to AKI is discussed in in a process that eventually may lead to thrombotic microangiopathies, necrotizing and crescentic GN, acute tubular necro- organ failure.10 The same process can be sis, and infective pyelonephritis or sepsis. Potential new avenues are further dis- initiated by inflammation but often the cussed for abrogating necroinflammation-related kidney injury, and questions and initial insult is not as obvious as in a gout strategies are listed for further exploration in this evolving field. attack. Monosodium urate crystals trig- ger IL-1b secretion and induce death in J Am Soc Nephrol 27: 27–39, 2016. doi: 10.1681/ASN.2015040405 .11,12 death im- plies the release of proteases, DNA, and histones that trigger inflammation of the Tissue injury and inflammation are tightly and inflammation.5–9 The very recent dis- joint structures, which recruits more linked and can cause each other.1 Infec- covery of the numerous forms of regu- neutrophils that die and so on.11,12 Clin- tious, toxic, or traumatic injuries usually lated necrosis gives rise to such a theory, ically, this process presents as a sudden result in tissue inflammation, and in turn, herein referred to as necroinflamma- onset of arthritis and sometimes even as fl autoimmune inflammation causes tissue tion.1,6,10 Necroinflammation integrates fever and acute illness, when in amma- injury. However, what are the molecular several concepts on the causal links be- tion reaches systemic dimensions.11 Sim- mechanisms underlying these bidirec- tween tissue injury and necrosis. In this ilarly, in stroke, myocardial infarction, or tional causalities? Immunity-related cell review, we discuss the definition of necro- acute tubular necrosis, the number of death involves the complement system or inflammation and its functions, molec- cells dying from the initial insult may be fl cytotoxic T cells as effector mechanisms ular pathways involved, contribution to few, whereas the subsequent in ammatory of infection and autoimmunity.2,3 Vice kidney disease, and strategies to thera- response contributes to further cell death versa, cell death–related immunity is best peutically disrupt necroinflammation explained by the recently discovered par- to limit kidney injury and failure. Published online ahead of print. Publication date adigm of dying cells releasing danger- available at www.jasn.org. associated molecular patterns (DAMPs) that trigger innate immunity via pattern WHAT IS NECROINFLAMMATION? Correspondence: Dr. Hans-Joachim Anders, Medi- zinische Klinik und Poliklinik IV, Klinikum der Uni- recognition receptors (PRR) (Supple- versität München, Ziemssenstr. 1, D-80336 München, mental Material).4 However, somehow Necroinflammation describes an au- Germany. Email: [email protected] fi these two concepts coexist in parallel toampli cation loop driven by necrosis Copyright © 2016 by the American Society of and still lack a unifying theory on injury (defined by cell death involving rupture Nephrology

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Table 1. Necrosis-related DAMPs and alarmins and their PRRs DAMPs Released by Receptors References Alarmins Receptors References Cytosol IL-1a IL-1R 112,113 HSPs TLR2/4 114 IL-33 ST2 115,116 Uric acid NLRP3, CLEC12a 12,117,118 TNF-a TNFR1/2 119,120 S100A, S100B RAGE 121 Nucleophosmin — 122 TLR4 123,124 SAP-130 MINCLE 125 F-actin CLEC9A 126 Granulysin, Defensin cathelicidin, EDN — 54,127 Mitochondria Neuropeptide PAR2 128 mtDNA TLR9 129 Tryptase — 130 ATP NLRP3 131,132 Cytochrome C — 133 N-formyl peptide FPR-1 129 Nucleus DNA, RNA, U1snRNP TLR7/8/9 134–137 AIM2 138 HMGB1 TLR2/4 139 Histones TLR2/4 74,103 NLRP3 105 TFAM RAGE 140 Necrotic tubule Uromodulin TLR4, NLRP3 141,142 HSP, heat shock protein; mtDNA, mitochondrial DNA; U1snRNP, U1 small nuclear ribonucleoprotein; HMGB1, high-mobility group box protein 1; TFAM, mitochondrial transcription factor A; CLEC12a, C-type lectin 12a; FPR-1, n-formyl peptide receptor-1; RAGE, receptor for advanced glycation end products; AIM2, absent in melanoma 2; EDN, eosinophil-derived neurotoxin; MINCLE, inducible Ca++-dependent C-type lectin; PAR2, protease-activated receptor.

(i.e., unnecessary collateral tissue damage). confirmed by the discovery of dying following six appear as the most appro- However, why did evolution favor such a cell-released DAMPs during sterile inju- priate to be distinguished for the purpose devastating mechanism? ries (Table 1).4 PAMPs and DAMPs are of this review. It is of note that in failing Janeway and Medzhitov proposed integrated at the level of the same PRRs organs, a single one of these pathways may the concept that pathogens activate in- that translate danger recognition into predominate, but often they overlap and nate immunity,13 which was subse- innate immune activation.7 This ex- trigger each other. For more detailed in- quently confirmed on the discovery of plains why, for example, gouty arthritis formation on the different categories of the various types of PRRs and their is clinically indistinguishable from regulated cell death, we refer the reader to pathogen-associated molecular pat- bacterial arthritis.4,19,20 Together, this excellent recent reviews.1,21 terns (PAMPs).14 From this example it suggests that necroinflammation is an Necroptosis is defined by the receptor- is obvious that the danger control autoamplification loop of necrosis and interacting protein kinase 3 (RIPK3)– program of inflammation was selected inflammation that evolved as a life-sav- mediated phosphorylation of mixed-lineage during evolution to at first combat ing mechanism of host defense but cau- kinase domain-like (MLKL),22 which by pathogens. Pathogen entry implies a dis- ses unnecessary tissue damage in sterile unknown means leads to plasma mem- rupted barrier to the outside (e.g., diseases. brane rupture.23 Numerous signaling wounded skin or a corneal, oral, or in- events can trigger RIPK3 phosphorylation, testinal ulceration). In this setting, especially a change of the RIPK1 poly- inflammation not only kills invaded NECROINFLAMMATION ubiquitination pattern that may be ini- pathogens but also provides a functional INVOLVES MULTIPLE MOLECULAR tiated downstream of several cell surface barrier to prevent further pathogen entry PATHWAYS receptors. Necroptosis has been well de- until re-epithelialization regenerates a scribed to kill parenchymal cells of all structural barrier to the outside.15,16 In- Categories of Regulated Necrosis tissues, including renal tubular epithelial flammation kills host cells at the site of Both apoptosis and necrosis are executed cells.22 TNF receptor 1 activation can infection to attack intracellular patho- in a regulated manner; however, necrosis trigger apoptosis and necroptosis, but the gens,7 which despite some collateral tis- especially alerts innate immunity because latter is favored in case of caspase deacti- sue injury, as a net impact, usually helps therupturedplasmamembraneinvolves vation.24 Meanwhile, the first negative host survival.7 Matzinger insisted that massive DAMP release into the extracel- regulator of necroptosis has been de- also sterile dangers alert the innate lular space. Many pathways of regulated scribed. Protein phosphatase 1b dephos- immune system,14,17,18 which was necrosis have been implicated, but the phorylates phosphorylated RIPK3, which

28 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 27–39, 2016 www.jasn.org BRIEF REVIEW thereby loses its ability to activate MLKL- maintain foot processes and to adhere to Retinoic Acid Inducible Gene–like mediated membrane rupture.25 the filtration barrier once forced to retract Receptors Ferroptosis is characterized by a de- their cytoskeleton from the foot processes Retinoic acid inducible gene–like recep- fined lipid peroxidation signature in to form the mitotic spindle.49–52 Another tors (RLRs) are intracellular receptors oxylipidomics analysis caused by a fail- example is the necessity to delete cells with for viral nucleic acids. RLRs signal ure of glutathione-peroxidase 4 func- significant cell damage in the early injury through adapter protein IFNb promoter tion.26,27 Ferroptosis involves ER stress phase of AKI.53 stimulator-1, resulting in IRF3 and NF- and dysfunction caused by a lack of glu- kBactivation.56 RLRs detect mostly rep- tathione,28,29 which may be induced How Necrosis Induces Inflammation licating viruses58; therefore, their role in by inhibition of the cellular Cys/Glu- Necrotic cells release DAMPs and alar- the recognition of endogenous nucleic antiporter System Xc-, which may be con- mins from several intracellular compart- acids is questionable. trolled by p53 via SLC7A11 or heat shock ments (Figure 1, Table 1). Alarmins are a protein beta 1.30,31 Ferroptosis can occur heterogeneous group of preformed C-type Lectin Receptors in any glutathione-depleted cell and has proinflammatory molecules that are re- C-type lectin receptors (CLRs) are sur- also been described in renal tubular ep- leased by cell death from stores inside the face receptors that can induce two dif- ithelial cells.27,32 cell.54,55 By contrast, DAMPs are mole- ferent pathways: CLEC4C, CLEC4E, Mitochondrial-permeability transition- cules with other proinflammatory func- CLEC5A, and CLEC6A are associated with mediated regulated necrosis (MPT-RN) tions under normal conditions that turn and induce signaling pathways through is independent of ferroptosis or necrop- into danger signals only once being re- ITAM-containing adaptor molecules, such tosis because it depends on cyclophilin leased by cell death and by alerting the as FcRg or DAP12. Other CLRs (e.g., D and may partially overlap with a poly innate immune system via a group of dectin-1, DC-SIGN, CLECL12A) induce (ADP-ribose) polymerase 1–mediated path- PRRs on the surface or inside other cells. signaling pathways through the activa- way of regulated necrosis, previously re- tion of protein kinases or phosphatases. ferred to as parthanatos. Both MPT-RN32-35 Toll-like Receptors CLR signaling mainly activates or mod- and parthanatos36–39 have been particu- Toll-like receptors (TLRs) are single trans- ulates NF-kBfunctions.59 larly worked out in renal cells and have membranereceptorscontainingacytosolic been reviewed elsewhere.40,41 Toll/IL-1 receptor interaction domain. On How Inflammation Induces Necrosis Pyroptosis is a consequence of DAMP binding, TLR homo- or heterodi- DAMPs released by dying cells activate inflammasome-driven caspase-11 acti- merization supports the recruitment of the PRRs on infiltrating immune cells, vation.42,43 Concomitant caspase-1 ac- specific cytosolic adapter molecules, such such as dendritic cells, , tivity induces mature IL-1b and IL-18 as myeloid differentiation primary re- neutrophils, and lymphocytes, and in- secretion, rendering pyroptosis partic- sponse gene 88, TRIF, TRAM, or TIRAP, trinsic renal parenchymal cells, and in- ularly inflammatory.42 Pyroptosis has to the Toll/IL-1 receptor domain, which duce the expression and local release of been clearly documented in infected mac- activates a set of kinases and transcription numerous proinflammatory mediators rophages and dendritic cells, and if py- factors, including NF-kB, activating pro- (Figure 1).60 In particular, TNF-a and roptosis can occur in renal cells is under tein-1, or IFN-related factors.56 IFN-g can induce necroptosis via two debate.44,45 distinct pathways. TNFR1 activation by NETosis is a controlled and often NOD-like Receptors TNF-a or TRIF activation via TLRs af- suicidal act of activated neutrophils, NOD-like receptors (NLRs) are intracel- fects the polyubiquitination of RIPK1, which results in the formation of neu- lular PRRs detecting danger signals in the which activates the kinase domain and trophil extracellular traps (NETs), con- cytosol. Among all NLRs, NOD-like re- induces the phosphorylation of RIPK3 sisting of expelled chromatin loaded with ceptor protein 3 (NLRP3) is specifically and subsequently of MLKL,61–63 whereas lysosomal and cytosolic proteases.46 The involved in DAMP recognition. For ex- IFN-g signals use a STAT3-protein ki- involved signaling pathways have not yet ample, uric acid and ATP activate NLRP3 nase R-dependent pathway to induce been fully understood but include to bind to its adapter molecule, adapter necroptosis.22 In this process RIPK1 NADPH-dependent ROS production protein apoptosis associated speck-like serves as a negative regulator to TNF- and RIPK1 signaling.47 protein containing a CARD, which both a–mediated cell death via caspase-8.21 Another avenue of cell death is mitotic form a caspase-1–activating complex, TNF-a and IL-8 can also induce NETosis catastrophe. When cells are forced to named the inflammasome.57 Caspase-1 in neutrophils.46,64 NET formation in- overcome the G2/Marrest of the cellcycle activation cleaves pro–IL-1b and pro– volves the release of histones, which elicit despite significant DNA damage, aber- IL-18 and induces the secretion of the cytotoxicimpactonendothelialcells, rant division of (i.e., an- mature . Both cytokines fur- mesangial cells, and podocytes, a process euploidy) renders the cell to death (i.e., ther induce innate immunity via their that is poorly defined at the molecular often necrosis).48–53 This is obvious in respective cytokine receptors (i.e., IL- level.65 Extracellular histones do not podocytes that impair their capacity to 1R type 1, IL-18Rs).56 seem to kill cells via a specificsurface

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Figure 1. Molecular pathways involved in necroinflammation. Necrotic renal cells release DAMPs and alarmins that activate DAMP or alarmin receptors on immune (and parenchymal) cells, respectively (Table 1). Activation of immune (and parenchymal) cells induces the secretion of numerous proinflammatory cytokines that in turn can induce several forms of regulated necrosis (e.g., necroptosis, pyroptosis). The necroptosis signaling pathway involves auto- and transphosphorylation of RIPK1 and RIPK3 and the recruitment of MLKL. Activation of caspase-1 induces release of IL-1b and IL-18, which causes inflammation. Certain DAMPs and proinflammatory cytokines, such as TNF-a or IL-8, directly activate neutrophils for the formation of NETs. NET formation expels large amounts of histones into the extracellular space. Extracellular histones have direct cytotoxic impact on renal cells and in addition induce TLR2-/ TLR4- and NLRP3-related immune cell activation. GPX-4, glutathione peroxidase; MOMP, mitochondrial outer membrane per- meabilization; p-MLKL, phospho-mixed lineage kinase domain-like; Ripk1, receptor-activating protein kinase 1; Ripk3, receptor-activating protein kinase 3. receptorbutratherinacharge-dependent reaches the kidney, infective pyelone- platelets, which imply disseminated in- manner.65 Furthermore, PAMP- or phritis triggers a potent inflammatory travascular coagulation, tissue hypoper- DAMP-induced NLRP3 activation not response for host defense.69,70 Patho- fusion, and organ dysfunction (e.g., of the only triggers cytokine release but also gen entry into the renal parenchyma lung, intestine, heart, kidneys).65,73,74 pyroptosis.42 An inactive pro–caspase-1 involves LPS-/TLR4-mediated patho- These mechanisms of remote disease ex- is synthesized on TLR activation, and ac- gen recognition and (C-X-C acerbation apply to any source of sepsis tivated NLR inflammasome complexes motif) ligand 12–driven neutrophil re- or trauma.75,76 Massive local DAMP or cleave pro–caspase-1 into its active form. cruitment, which can cause abscess for- histone release can cause remote micro- Hence, it is considered as an infection- mation and massive renal cell necrosis.71 vascular injuries and clotting (e.g., in the induced cell death.42,66 Together, several Necrosis disrupts internal barriers and lung), which serves as a pathophysiologic proinflammatory signals induce regu- promotes pathogen spreading and uro- explanation to acute respiratory distress lated necrosis. sepsis.71 Circulating bacterial endotoxin syndrome in such settings.76 is a potent stimulus for cytokine release from monocytes and other immune and Acute Tubular Necrosis NECROINFLAMMATION IN nonimmune cells, which has been re- Ex vivo microscopy (high-resolution KIDNEY DISEASE ferred to as a cytokine storm.67,72 In microscopy of freshly isolated primary this process, cytokine-induced NETosis kidney tubules) revealed how single-cell Sepsis Urosepsis and histone release can occur every- necrosis can spread on neighboring Local immune responses disrupting ep- where in the microvasculature, which cells so that the entire tubule segment ithelial and mesenchymal barriers can is indicated by increased levels of histones undergoes a synchronized cell death.35,77,78 facilitate pathogen spreading into the in the circulation of septic patients.73,74 Whether synchronized necrosis occurs in circulation (i.e., sepsis).67,68 For example, Circulating histones cause cytotoxic im- vivo has yet to be demonstrated. Regu- when ascending urinary tract infection pact to endothelial cells and activates lated tubule necrosis is not limited to

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Table 2. Regulated necrosis pathways tested in different models of acute tubular domain or caspase-835; second, necrosta- necrosis tins do not protect isolated renal tubules RN In Vivo/Ex from ischemic injury. In contrast, inhibi- ATN Protection Reference Pathway Vivo tion of ferroptosis is very effective in pro- Ischemic renal injury Necroptosis In vivo Yes 34,78 tection from ischemia-reperfusion injury Ex vivo No 78 in vivo and hydroxychloroquine-/iron- Ferroptosis In vivo Yes 32 induced tubular damage ex vivo.32 There- MPT In vivo Yes 33,34 fore, the primary mode of tubular cell death Delayed graft function Necroptosis In vivo Yes 77 inthesemodelsisstilluncertain(Figure2). Cisplatin nephrotoxicity Necroptosis In vivo Yes 36,81 Even MPT-RN appears to contribute to 82 Rhabdomyolysis Necroptosis In vivo Yes tubular injury, either directly or indi- Contrast media related Necroptosis In vivo Yes 83 fi 84 rectly. Combined de ciency of cyclophilin Adriamycin nephrotoxicity Necroptosis In vivo Yes fi 32 D and RIPK3 led to highly signi cant sur- Hydroxychloroquine/iron induced Ferroptosis Ex vivo Yes fi Calcium oxalate crystals related Ferroptosis In vivo Yes 32 vival bene ts,eveninseveremodelsof Necroptosis In vivo Yes Unpublished data post-ischemic tubular necrosis, suggest- ing that MPT-RN and necroptosis addi- tively contribute to tubular necrosis.33,34 post-ischemic AKI35,79 or delayed graft tubular necrosis and survival is attenu- In turn, inflammation is an important ac- function,77,80 but cisplatin nephrotoxi- ated in Ripk3-deficient mice,84 but celerator of tubular injury15,85 and involves city involves necroptosis of tubular cells, whether tubular cells themselves directly potential triggers of necroptosis such as triggering necroinflammation35,81 (Table die via necroptosis, or succumb to some TNF-a.86,87 Oxalate crystal formation 2). The same process causes tubular ne- other cell death secondary to initial inside tubules induces RIPK3- and crosis in rhabdomyolysis.82 In addition, RIPK3-mediated hypoperfusion, is MLKL-dependent tubular cell death contrast media–related renal dysfunction still a matter of debate. First, tubules can- (S.R. Mulay and H.-J. Anders, unpublished is entirely reversible by necrostatin-1.83 not be sensitized to necroptosis by the loss data), and the associated ATP release Moderate-dose adriamycin-induced of Fas-associated protein with death from dying tubular cells triggers NLRP3

Figure 2. Necroinflammation in glomerular and tubulointerstitial inflammation. (A) Neutrophil extracellular trap formation in glomerular capillaries (e.g., in ANCA vasculitis) causes histone-related endothelial cell death and subsequent capillary loop necrosis. DAMP release activates other glomerular cells to produce cytokines and , which recruit more cytokine-producing leukocytes, including neutrophils undergoing NETosis. TNF-a and histones drive further necrosis of glomerular cells. The associated rupture of the glomerular basement membrane implies not only podocyte injury but also plasma leakage into Bowman’s space. Plasma components such as fibrinogen activate parietal epithelial cell hyperplasia and crescent formation. (B) In tubule injury, regulated necrosis of any kind may be the initial event. Histones released by tubular cells and netting neutrophils elicit direct cytotoxicity. The associated release of DAMPs and alarmins induces inflammation, which implies the recruitment of cytokine-producing leukocytes into the peritubular interstitium. Also, TNF-a and possibly other cytokines drive necroptosis as a secondary cell death category contributing to tubular necrosis and renal dysfunction. This sets up the auto-amplification loop of necroinflammation.

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Table 3. Some molecular targets to therapeutically interrupt necroinflammation Molecular Target Primary Effect Compounds Reference Regulated necrosis RIPK1 Stabilizing RIPK1 Necrostatins, ponatinib 143 RIPK3 Blocking phosphorylation of MLKL GSK872, GSK840 144 Dabrafenib 145 pMLKL Unknown Necrosulfonamide 146 Cyclophilin D Preventing mitochondrial membrane Sanglifehrin A, cyclosporin A 35 potential–related necrosis PARP1 Inhibiting PARP-1–driven parthanatos Olaparib 147 GPX4 GPX4 blocks ferroptosis 26,27 Lipid peroxidation Loss of plasma membrane integrity Ferrostatins 32 Liproxstatin-1 27 Complement C5a Blocking complement-mediated Eculizumab plus others 148–151 inflammation and injury Properdin Blocking alternative complement MAb 1340 152 pathway–related inflammation Chemokines/CCRs CCL2/CCR2 Blocking leukocyte recruitment NOX-E36, RS504393 153,154 CXCR3 Blocking leukocyte recruitment VUF10085 155 Numerous CK Blocking leukocyte recruitment TAK-779, NR58–3.14.3 155–158 Cytokines TNF-a Blocking TNF-mediated cell death Infliximab plus others 110,159–161 and inflammation IL-1b Blocking IL-1R–mediated immunity Anakinra plus others 88,162–166 IL-6 Blocking IL-6–mediated immunity Tocilizumab plus others 167–170 IL-17 Blocking IL-17–mediated immunity Secukinumab plus others 171–173 Anti-TWEAK Blocking TWEAK-mediated immunity RG7212, 174 BIIB023 175,176 Jak-STAT Blocking cytokine-driven immunity AG490, S3I-201, ruxolitinib, tofacitinib 177,178 179

180 DAMPs Histones Blocking histone cytotoxicity and Antihistone IgG 74,92,103 TLR2/TLR4/NLRP3 activation Activated protein C Heparin PRRs TLR2, TLR4, TLR7, TLR9 Blocking TLR-driven immunity OPN-305, IMO-8400 181–183 NLRP3 Blocking inflammasome-driven IL-1b/IL-18 Glyburide 184 release and caspase-1–driven pyroptosis VX-765, MCC950 185,186 b-hydroxybutyrate 187 RIPK1, receptor-activating protein kinase 1; pMLKL, phospho-mixed lineage kinase domain-like protein; PARP-1, poly (ADP-ribose) polymerase 1; GPX4, glutathione peroxidase 4; CCR, chemokine (C-C motif) receptor; CCL, chemokine (C-C motif) ligand; CXCR3, chemokine (C-X-C motif) receptor 3; CK, chemokines; TWEAK, TNF-like weak inducer of apoptosis; Jak-STAT, Janus kinase and Signal Transducer and Activator of Transcription; PRR, pattern recognition receptors; MAb, monoclonal antibody. inflammasome activation, IL-1b–dependent in the transplanted organ after reperfusion glomerular endothelial cell necrosis renal inflammation, and renal failure in and in the lungs of the recipients. (Figure 2).91 For example, in experimental mice.88 Blocking either necroptosis with antiglomerular basement membrane necrostatin-1 or IL-1 with anakinra can Rapidly Progressive GN disease, neutrophils undergo NETosis in- abrogate kidney injury and dysfunction88 Rapidly progressive GN usually pres- side the glomerular capillaries. It is the re- (S.R. Mulay and H.-J. Anders unpub- ents as necrotizing and crescentic GN, lease of histones that induces glomerular lished data). ATN-associated release of which are classic presentations of ANCA- endothelial cell necrosis.92 This became proinflammatory cytokines, DAMPs, and associated vasculitis, lupus nephritis, anti- obvious because either the specific inhi- other components may also cause remote glomerular basement membrane disease, bition of NETosis or the neutralization of tissue injury.80,89 These authors detected or Henoch–Schonlein purpura.90 Mecha- extracellular histones abrogated crescentic parthanatos, necroptosis, and MPT-RN nistically, necrotizing GN develops from GN.92 Similarly, NETs are also found in

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Table 4. Necroinflammation Open Questions What determines the dynamics of transient versus persistent and local versus systemic necroinflammation? Does expression of NLRP3 and ASC in renal cells also imply the possibility for pyroptosis? Are there endogenous inhibitors of regulated necrosis in addition to MLKL phosphatase? Is regulated necrosis controlled by miRNAs, epigenetics, metabolic status...? Do gene variants in regulated necrosis-related genes determine clinical phenotypes? Are there more forms of regulated necrosis? Which signaling molecules are involved? Are there kidney- or renal cell–specific pathways of regulated necrosis? What is the relative contribution of regulated necrosis pathways to organ damage in AKI? Is the role of apoptosis restricted to physiologically occurring events in the kidney? Are there any pathophysiologies mediated by apoptosis? What is the role of necroinflammation in CKD? What is the role of apoptosis versus regulated necrosis inside the kidney? Is it sufficient to block either necrosis or inflammation to suppress necroinflammation or do respective inhibitors have synergistic additive effects when given in combination? Can we prevent delayed graft function or other forms of expected AKI by preemptive cell death inhibitor prophylaxis in high-risk patients? How broad is the therapeutic window to prevent full-blown AKI? What are the risks of short-term or long-term cell death inhibitor exposure? Will inhibition of primary necrosis in transplants lead to less priming of memory B cells in the first moment at reperfusion and reduce the rate of long- term antibody-mediated rejection? Which Food and Drug Administration–approved drugs in every day clinical use, other than cyclosporin and ponatinib, interfere with regulated necrosis? ASC, adapter protein apoptosis associated speck-like protein containing a CARD; miRNAs, microRNAs. necrotic glomerular lesions in human uncontrolled complement activation- initial trigger of TMA.100 Long-term out- renal vasculitis.93 Complement-mediated induced atypical hemolytic uremic syn- comes of renal TMA depend on each cell cytotoxicity is another trigger for glo- drome, preeclampsia, systemic sclerosis, type’s capacity to repair from intrinsic or merular necroinflammation.94 Glomer- malignant hypertension).100 In other extrinsic progenitor reservoirs.106 ular cell necrosis induces DAMP release forms of TMA, an inappropriate activa- that further drives cytokine and chemo- tion of clotting initiates the process (e.g., kine release, leukocyte recruitment, and antiphospholipid syndrome, ADAMTS13 TARGETING RENAL inflammation.92 Infiltrating immune deficiency).100 Independent of the trig- NECROINFLAMMATION FOR cells, in turn, further contribute to necro- gering mechanism, TMA involves an au- PROPHYLAXIS AND THERAPY inflammation by NETosis (neutrophils),92 toamplification loop of tissue necrosis and cytokine-induced cell death (all proin- inflammation.100 Thrombosis involves If necroinflammation is an autoamplifi- flammatory leukocytes),95 or direct T a massive release of cytokines and che- cation loop, blockade of either compo- cell–related cytotoxicity.96 Vascular wall mokines from platelets that activate en- nent should be sufficient to decelerate rupture not only facilitates hematuria dothelial cells and recruit leukocytes to and potentially abrogate it. This is well but also plasma leakage as a major driver the site of injury, a process referred to documented by numerous experimental of parietal epithelial cell hyperplasia and as immunothrombosis.101 Circulating studies of inhibiting different molecular crescent formation.97 Therefore, NETosis neutrophils get increasingly involved targets that still fully abrogate experi- and histone or complement cytotoxicity and contribute to thrombus formation mental AKI (Table 3).107 For example, triggering glomerular necroinflamma- via NET formation,102 which is associated prophylactic therapy with a combina- tion are a central pathomechanism of with local histone release. Extracellular tion of three different cell death inhibitors rapidly progressive GN related to histones elicit three different impacts: (ferrostatins, necrostatin-1, sanglifehrin A) ANCA-associated vasculitis and the they kill microvascular endothelial prevents kidney injury, inflammation, other forms of necrotizing GN.98,99 cells,74,92,103 trigger platelet activation and and dysfunction in models of ultra- further thrombosis,104 and activate in- severe duration of ischemia before reper- Thrombotic Microangiopathy nate immunity via TLRs and the NLRP3 fusion.35 Along these lines, preventing Thrombotic microangiopathy (TMA) can inflammasome.103,105 As a proof of prin- NETosis with a PAD4 inhibitor or extra- be initiated by various triggers, which all ciple, histone injection into the renal ar- cellular histone neutralization abrogates share endothelial cell injury-related micro- tery induces widespread TMA and renal crescentic GN.92 Autoacceleration of vascular thrombosis and organ dysfunc- cell necrosis.103 Currently, this auto- necroinflammation implies that the tion.100 In some disorders, endothelial cell amplification loop of microvascular in- time point of intervention is of critical injury is the primary event (e.g., Shiga toxin- jury, thrombosis, and inflammation can importance. Only preemptive blockade induced in hemolytic uremic syndrome, only be terminated by abrogating the of necroinflammation can be maximally

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1 2 3 GLOSSARY 4 5 DAMPs Danger/damage-associated molecular patterns are molecules with certain functions 6 7 during homeostasis that turn into an immunostimulatory or cytotoxic alarm signal 8 9 once injury misplaces them out of their natural compartment, i.e. extracellular 10 11 histones or Tamm-Horsfall protein leaking from injured tubules. 12 13 14 Danger control Response programs such as clotting, inflammation, regeneration, and scarring that 15 16 were positively selected by evolution because they limit potentially fatal dangers 17 18 such as bleeding, infection, barrier dysfunction, and tissue instability, respectively. 19 20 Inflammation Local or systemic expression of cytokines that activate endothelial cells. This implies 21 22 vascular plasma leakage and recruitment of activated leukocytes to enforce killing of 23 24 pathogens, if present. Collateral tissue injury is particularly obvious in the absence of 25 26 27 pathogens, i.e. sterile inflammation. Systemic inflammation may present with fever 28 29 or as shock. 30 31 Adaptive immunity Antigen-induced and -specific Immune response based on antigen- 32 33 presentation and antigen-specific B and T cells. 34 35 Innate immunity Genetically determined, intrinsic mechanisms of host defence. 36 37 Necrosis Mode of cell death characterized by the rupture of the plasma membrane. 38 39 40 Necroinflammation An auto-amplification loop of cell necrosis and inflammation that is driven by 41 42 DAMP-release of necrotic cells and inflammation-related regulated necrosis. 43 44 PAMPs Pathogen-associated molecular patterns activate immune and parenchymal cells via 45 46 specific pattern recognition receptors, i.e. bacterial endotoxin/LPS activating Toll-like 47 48 receptor-4. 49 50 Regulated necrosis Active forms of necrosis induced via specific signalling pathways. Such 51 52 53 pathways can be activated from outside the cell (outside-in) via distinct surface 54 55 receptors or from inside the cell during cell stress. Blocking these pathways prevents 56 57 necrosis. 58 59 60 3

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