Necroinflammation in Kidney Disease
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BRIEF REVIEW www.jasn.org 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 cytokine 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 innate immune system, 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 neutrophils.11,12 Neutrophil 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 J Am Soc Nephrol 27: 27–39, 2016 ISSN : 1046-6673/2701-27 27 BRIEF REVIEW www.jasn.org 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, macrophage 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