Physiol Rev 98: 727–780, 2018 Published February 21, 2018; doi:10.1152/physrev.00041.2016 ORIGIN AND CONSEQUENCES OF NECROINFLAMMATION Maysa Sarhan, Walter G. Land, Wulf Tonnus, Christian P. Hugo, and X Andreas Linkermann Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg, Strasbourg, France; German Academy of Transplantation Medicine, Munich, Germany; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and Consequences of Necroinflammation. Physiol Rev 98: 727–780, 2018. Published February 21, 2018; doi:10.1152/physrev.00041.2016.—When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immuno- genic intracellular molecules and organelles into the interstitium and thereby represent the Lstrongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflamma- tion can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each partic- ular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions. I. GENERAL INTRODUCTION 727 lular content is released as damage associated molecular II. REGULATED NECROSIS 732 patterns (DAMPs). As a consequence of necrosis, DAMPs III. A CLASSIFICATION OF DAMPs 741 bind to different molecules on various other cells IV. DAMP-INDUCED INNATE ALLOIMMUNITY 745 in the interstitium. Here, we provide a classification of V. DAMP-INDUCED PATHWAYS... 751 DAMPs which is suggested in TABLE 1. As a mechanistic VI. A MODEL FOR THE IMMUNOLOGICAL ... 755 basis for this classification, we recommend the DAMP VII. ROLE OF DAMPs IN ... 756 sensing as a differentiation criterion. With our increasing VIII. PERSPECTIVES FOR CANCER AND ... 758 understanding of the distinct signaling pathways of reg- IX. SUMMARY ON ORIGIN AND ... 759 ulated necrosis, a growing body of evidence suggests that RN pathways trigger different immune responses. There- fore, a given RN pathway may specifically fine tune the I. GENERAL INTRODUCTION immune response for specifc needs to regenerate a given tissue or to fight given microbes more effectively. Differ- ences in necroinflammation may therefore explain why A. The Concept of Necroinflammation several distinct cell death pathways are conserverd in our genome. In this review, we discuss the cell death pathways (Origin) and different classes of DAMPs (Consequences) of necroin- flammation. We define necroinflammation as the immune B. General Introduction to Regulated response to necrosis in a living organism. Necrosis is exe- Necrosis cuted as a regulated process through defined signaling path- ways such as necroptosis, ferroptosis, and pyroptosis or Necrosis generally does not occur in an uncontrolled man- may happen in a nonregulated fashion as traumatic necrosis ner, at least not in nontraumatic diseases. Instead, it follows (FIGURE 1). Whenever a cell undergoes necrosis, its intracel- genetically determined signaling pathways. The cell death 0031-9333/18 Copyright © 2018 the American Physiological Society 727 Downloaded from www.physiology.org/journal/physrev by ${individualUser.givenNames} ${individualUser.surname} (157.139.021.001) on February 22, 2018. Copyright © 2018 American Physiological Society. All rights reserved. SARHAN ET AL. Necroinflammation Origin Consequences FIGURE 1. Origin and consequences of dying cell necroinflammation. Necrosis is executed as DAMP Ia → PRR a regulated process through defined signal- Necroptosis DAMP Ib → P2x7 ing pathways such as necroptosis, ferropto- sis, and pyroptosis or may happen in a non- regulated fashion as traumatic necrosis. Ferroptosis Whenever a cell undergoes necrosis, its in- DAMP II → NLRP3 tracellular content is released as damage- associated molecular patterns (DAMPs). As Pyroptosis a consequence of necrosis, DAMPs bind to DAMP III → NKG2D different molecules on various other cells in the interstitium. For a classification of Traumatic necrosis DAMPs which is suggested in TABLE 1 of this review, we recommend the DAMP sens- DAMP IV → IgM → Complement ing as a means of classifying DAMPs. In this review, we will discuss the cell death path- ways (Origin) and different classes of DAMPs (Consequences) of necroinflammation. We DAMP V → UPR define necroinflammation as the immune re- sponse to necrosis in a living organism. DAMP VI → GPR91 community has been addressing the question of uncon- molecules, including pro- and anti-inflammatory cyto- trolled cell death for decades, thereby uncovering the mo- kines. Proteases are very active in some necrotic type cell lecular pathways of regulated necrosis (RN). Many RN death subroutines and process long-lasting cytokines, pathways have been described, and it is a major task to such as Pro-interleukin (IL)-1␤ and Pro-IL-18 in case of unravel the overlapping and indistinguishable features of pyroptosis. When such cells, often macrophages, finally these pathways. This problem required some consensus on undergo pyroptosis, the immunogenicity is not limited to the definitions used that have been summarized in the the standard cytosolic arsenal of DAMPs, but contains Guidelines of the Nomenclature Committee on Cell Death, some additional cytokines that enhance the immunoge- the most current version of which being in line with this nicity beyond the level of default DAMP release. In con- review (181). trast, active transcription of IL-33 during necroptosis stabilizes regulatory T cells in the surrounding microen- Necrosis, defined by plasma membrane rupture (PM-rup- vironment and thereby functionally dampens the immune ture), inevitably results in death of a particular cell. At this response (540, 570). Analyzing these factors for each cell point the cell is dead by definition. As a consequence of death subroutine, we will introduce a hierarchy for im- PM-rupture, the intracellular content gains access to the munogenicity of necrotic cell death pathways in this re- interstitial space, to other cells, matrix components etc. The view. It is because of the immunogenicity of regulated accessibility of surveillance immune cells to mitochondria, necrosis that we should understand these pathways and lysosomes, peroxisomes, and other organelles suggests that interfere with them therapeutically as indirect, but puta- necrosis per se is a very immunogenic event. Intravital mi- tively highly potent immunosuppression. croscopy has visualized the process of necrosis in vivo (384), and DAMPs released during this process were in some cases referred to as cell death associated molecular C. General Introduction to DAMPs patterns (CDAMPs) (330). The amount of DAMPs released by a cell is probably much more immunogenic when com- 1. The danger/injury model in immunology pared with a single molecule on the surface of a living cell, e.g., the incompatibility of single proteins such as HLA- More than 20 yr ago, in January and April 1994, the danger mismatches and blood group antigens in the setting of hypothesis was first published proposing that a discrimina- transplantation. tion of the immune system between self and non-self does not sufficiently explain immune reponses. Its evolutionarily It is of interest to realize that the process of regulated determined driving force was proposed to become alarmed death takes some time. During this process, cells metab- and to react by any form of cell stress and/or tissue damage olize plenty of ATP to drive transcription of hundreds of including allograft injury. Two major considerations led to 728 Physiol Rev • VOL 98 • APRIL 2018 • www.prv.org Downloaded from www.physiology.org/journal/physrev by ${individualUser.givenNames} ${individualUser.surname} (157.139.021.001) on February 22, 2018. Copyright © 2018 American Physiological Society. All rights reserved. NECROINFLAMMATION Table 1. Classification of DAMPs involved in inflammation, adaptive immunity, and nociception Categories of Cognate Recognition Receptors/Sensors Classes of DAMPs* (Cell Bound, Humoral) Class Ia DAMPs ϭ DAMPs such as HMGB1, HSPs, nucleic Sensed via binding to “classical” recognition receptors acids including mitochondrial and cytosolic DNA (ϭ PRRs such as TLRs, RLRs, ALRs) on/in innate immune cells such as phagocytes including DCs, thereby