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Nephrologie 26. September 2016

Mediators of necroinflammation in kidney disease

Known since ancient times: tissue injury and inflammation often go together but what are the underlying molecular mechanisms? Inflammation triggers cell death via complement activation or cytotoxic T cells. Dying cells release molecules that trigger inflammation by activating pattern recognition receptors (PRR) of the innate immune system. This bidirectional relationship between inflammation and cell necrosis fuelling an autoamplification loop is referred to as necroinflammation (Fig.  1 ; [ 5 ]). Necroinflammation is accelerated by immunity-related cell necrosis and cell necrosis-related immune activation. Necroinflammation can be initiated by a few necrotic cells that activate the innate immune system, which subsequently leads to necrosis of more cells triggering more inflammation, a process that can eventually lead to organ failure (Fig.  1 ).

How inflammation can induce cell necrosis. Inflammation can trigger various forms of cell necrosis. For example, necroptosis involves receptor-interacting protein kinase 3 (RIPK3)-mediated phosphorylation of mixed-lineage kinase domain-like (MLKL) protein. Activation of MLKL can lead to necrosis by inducing rupture of plasma membranes. Numerous signalling events can trigger RIPK3 phosphorylation, for example, surface death receptor activation leading to a conformational change of RIPK1. Necroptosis is well-known to kill parenchymal cells of all tissues including renal tubular epithelial cells. Ferroptosis is characterized by a defined lipid peroxidation signature in oxylipidomics analysis caused by a failure of glutathione peroxidase 4 function. Ferroptosis involves a depletion of glutathione, which can be induced by inhibition of the cellular cystine/glutamate antiporter system xc controlled by p53 via SLC7A11 or heat shock protein beta 1 (HSPB1). Ferroptosis occurs in any glutathione-depleted cell including renal tubular epithelial cells. Mitochondrial permeability transition-mediated regulated necrosis (MPT-RN) is independent of ferroptosis and necroptosis as it depends on cyclophilin D and may partially overlap with a poly(ADP-ribose) polymerase (PARP1)-mediated pathway of regulated necrosis, previously referred to as parthanatos. Both MPT-RN and parthanatos have been in particular worked out in renal cells. Pyroptosis is a consequence of inflammasome-driven caspase 4/5/11 activation. Concomitant caspase-1 activity induces mature interleukin (IL)-1 beta and IL-18 secretion, rendering pyroptosis particularly immunogenic. Whether pyroptosis can occur in renal cells is currently unclear. NETosis is a controlled and often suicidal act of activated neutrophils, which results in the formation of neutrophil extracellular traps (NET) consisting of expelled chromatin loaded with lysosomal and cytosolic proteases.

How cell necrosis induces inflammation, a role for histones. Necrotic cells release damage-associated molecular patterns (DAMPs) and alarmins from several intracellular compartments. While alarmins are a heterogeneous group of mediators with different pro-inflammatory activities, DAMPs alert the innate immune system via Toll-like receptors (TLR), nucleotide oligomerization domain (NOD)-like receptors/inflammasomes and C‑type lectin receptors. The DAMPs released by dying cells activate the PRR on infiltrating immune cells, such as dendritic cells, macrophages, neutrophils and lymphocytes and induce the expression and local release of numerous pro-inflammatory mediators. In particular, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) can induce necroptosis via two distinct pathways. Activation of TNF receptor 1 (TNFR1) by TNF-alpha or activation of Toll/IL-1 receptor domain containing adaptor inducing IFN-beta (TRIF) via TLRs affects the conformation of RIPK1, which induces the phosphorylation of RIPK3 and MLKL, whereas IFN-gamma signals via a signal transducer and activator of transcription 3 (STAT3)-protein kinase R‑dependent pathway to induce necroptosis. TNFα and IL-8 can also induce NETosis in neutrophils. Extracellular histones have a central role in necroinflammation. NET formation and other forms of necrosis involve the release of histones, which elicit cytotoxic effects on endothelial and other cells. Extracellular histones do not seem to kill cells via a specific surface receptor but via their strong basic a charge that kills cells by disrupting their plasma membrane.

Which kidney diseases involve necroinflammation? The concept of necroinflammation can explain a number of clinical phenomena [ 1 ]. For example, when an ascending urinary tract infection affects the kidneys, host defence involves lipopolysaccharide TLR4 (LPS/TLR4)-mediated pathogen recognition and chemokine (C-X-C motif) ligand 12 (CXCL12)-driven neutrophil recruitment, which can cause abscess formation and massive renal cell necrosis. Necrosis disrupts internal barriers and promotes pathogen spreading and urosepsis. Circulating bacterial endotoxin is a potent stimulus for cytokine release from monocytes and other immune and non-immune cells, which has been referred to as a cytokine storm. In this process cytokine-induced NETosis and histone release can occur everywhere in the microvasculature, which is indicated by increased levels of histones in the circulation of septic patients. Circulating histones cause cytotoxic effects to endothelial cells and activate platelets, which implies disseminated intravascular coagulation, tissue hypoperfusion and organ dysfunction, e. g. of the lungs, intestines, heart and kidneys (Fig.  1 ).

Regulated tubular necrosis also occurs in post-ischemic or toxic acute kidney injury (AKI), delayed graft function or rhabdomyolysis. In these diseases inflammation is an important accelerator of tubular injury. Oxalate crystal formation inside tubules induces RIPK3 and MLKL-dependent tubular cell death [ 2 ] and the associated ATP release from dying tubular cells triggers activation of the NLR protein 3 (NLRP3) inflammasome, IL-1beta-dependent renal inflammation and renal failure in mice [ 3 ]. Also rapidly progressive glomerulonephritis (RPGN) usually presents as necrotizing and crescentic GN, which are classical presentations of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, lupus nephritis and anti-glomerular basement membrane (GBM) disease. For example, in experimental anti-GBM disease neutrophils undergo NETosis inside the glomerular capillaries and it is the release of histones that induces glomerular endothelial cell necrosis [ 4 ]. This becomes obvious as either the specific inhibition of NETosis or the neutralization of extracellular histones abrogated crescentic GN. Similarly, NETs are also found in necrotic glomerular lesions in human renal vasculitis. Complement-mediated cytotoxicity is another trigger for glomerular necroinflammation.

Necroinflammation is a theory that combines several concepts on kidney injury. Necroinflammation is a serial event of cell necrosis triggering inflammation and further regulated necrosis. If not treated at an early stage necroinflammation can lead to organ failure or even systemic inflammation and remote organ injury. By concept, either anti-inflammatory agents or cell death inhibitors can abrogate this process. This concept remains to be validated in patients.

Compliance with ethical guidelines

Conflicts of interest

H.-J. Anders states that there are no conflicts of interest.

The accompanying manuscript does not include studies on humans or animals.


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  3. Mulay SR, Kulkarni OP, Rupanagudi KV, Migliorini A, Darisipudi MN, Vilaysane A, Muruve D, Shi Y, Munro F, Liapis H, Anders HJ. (2013) Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion. J Clin Invest. 2013 Jan;123(1):236–46.
  4. SVKumarOPKulkarniSRMulayMNDarisipudiSRomoliDThomasovaCRScherbaumBHohensteinCHugoSMüllerHLiapisHJAnders 2015 Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN J Am Soc Nephrol 26 239924131:CAS:528:DC%2BC28XmtVersLs%3D 10.1681/ASN.2014070673 25644111 Kumar SV, Kulkarni OP, Mulay SR, Darisipudi MN, Romoli S, Thomasova D, Scherbaum CR, Hohenstein B, Hugo C, Müller S, Liapis H, Anders HJ (2015) Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J Am Soc Nephrol 26:2399–2413
  5. ALinkermannBRStockwellSKrautwaldHJAnders 2014 Regulated cell death and inflammation: an auto-amplification loop causes organ failure Nat Rev Immunol 14117597671:CAS:528:DC%2BC2cXhslKmu73J 10.1038/nri3743 25324125 Linkermann A, Stockwell BR, Krautwald S, Anders HJ (2014) Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol 14(11):759–767

Abb. 1.:  The vicious cycle of necroinflammation (with kind permission of Dr. Andreas Linkermann, University of Kiel, Germany)

Abb. 1.: The vicious cycle of necroinflammation (with kind permission of Dr. Andreas Linkermann, University of Kiel, Germany)

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