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Inflammasome activation in response to dead cells and their metabolites
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ScienceDirect Inflammasome activation in response to dead cells and their metabolites Hajime Kono1, Yoshitaka Kimura1,2 and Eicke Latz3,4,5 Cell death cannot go unnoticed. It demands that the surrounding cells clear away the corpses in a manner appropriate to the type of cell death. Dying cells represent a threat to the body that should be eliminated by the host immune response. Inflammasome activation followed by IL-1alpha release and IL-1beta maturation is crucial for tackling pathological conditions, including infections, whereas inflammasome activation precedes inflammatory pyroptotic cell death. On the other hand, recent studies have shown that the inflammasome plays an important role in the pathogenesis of metabolic diseases, including obesity, diabetes, and atherosclerosis. Here, we review current knowledge of the association between cell death, excess metabolites, and inflammasome activation as it relates to chronic inflammatory diseases. Addresses 1 Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan 2 Department of Allergy and Rheumatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan 3 Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany 4 Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA 5 German Center for Neurodegenerative Diseases, 53175 Bonn, Germany Corresponding author: Kono, Hajime ([email protected])
Current Opinion in Immunology 2014, 30:91–98 This review comes from a themed issue on Effects of endogenous immune stimulants Edited by Eicke Latz and Kensuke Miyake For a complete overview see the Issue and the Editorial http://dx.doi.org/10.1016/j.coi.2014.09.001 0952-7915/# 2014 Elsevier Ltd. All right reserved.
The way a cell dies matters more than the death itself Individual cells have a finite life span, and they are replaced with new ones after their demise. Only very few cell types last to the end of an individual’s lifetime. These long-lived cells include occipital neurons of the cerebral cortex, inner lens cells of the eyes, and muscle cells of the heart [1]. Moreover, the overall life span of cells varies by type. For example, intestinal epithelial cell www.sciencedirect.com
have an average life span of one day, while osteocytes can live for several years. At the end of a cell’s lifespan the cell usually dies from apoptosis. This form of cell death does not evoke an inflammatory response as it is part of the physiological cellular replacement which constantly occurs throughout life of multicellular organisms [2,3,4]. One of the most important factors determining whether cell death is inflammatory or not is the integrity of the plasma membrane [5,6]. If the plasma membrane integrity becomes compromised, hidden molecules inside cells — which are usually sequestered and not exposed to the extracellular milieu — are released. Some of these molecules exert pro-inflammatory activities in the extracellular space and are called damage-associated molecular patterns (DAMPs), or ‘danger signals’ [7,8]. In the early course of apoptosis the contents of the cell are not released and thus remain hidden from the extracellular environment. However, if apoptotic cells are not engulfed and cleared by adjacent cells or resident tissue macrophages in a timely manner, apoptotic cells become secondarily necrotic. In this situation, the integrity of the plasma membrane is lost and an inflammatory response is initiated [2]. Hence, apoptotic cells need to be recognized and their removal by the surrounding cells prevents an otherwise inflammatory reaction toward apoptosis (Figure 1). Once the plasma membrane has been damaged the DAMPs released from dead or dying cells can be recognized by local immune cells, such as macrophages or dendritic cells. Numerous innate immune signaling receptors can evoke inflammatory cascades toward DAMPs. In fact, most innate immune receptors, such as members of the Toll-like receptor (TLR) [9,10,11] or C-type lectin (CLR) families [12], that can recognize microbial substances can also respond to host derived danger signals. Hence our immune system is programmed to react to ourselves under certain situations. While at first sight counterintuitive, this mechanism could serve infection control against numerous kinds of pathogens [7,13]. With the limited sets germ-line encoded innate immune signaling receptors it may be challenging to recognize all types of pathogens. Mounting an inflammatory response to danger signals, which appear when the cellular integrity is perturbed by microbes or other means seems to be a feasible way of detecting invading microbes. In addition to a role of sensing cell death during infections, the inflammatory response to cell death also underlies the pathogenesis of many diseases in which cell death occurs in the absence of infection, including Current Opinion in Immunology 2014, 30:91–98
92 Effects of endogenous immune stimulants
Figure 1
death associated with distinct biochemical processes, similar to apoptosis. In comparison, cell death by oncosis and/or necrosis can occur accidentally without a defined biochemical process.
necrotic cell death
Necroptosis
DAMPs inflammasome activation
pyroptotic cell death
macrophage DAMPs inflammasome activation
IL-1 secretion macrophage
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Sequential inflammasome activation by necrosis and pyroptosis. Danger signals or DAMPs released from necrotic cells are recognized by macrophages in situ. Inflammasome-activated macrophages secrete IL1 family cytokines and fall in pyroptotic cell death. Pyroptotic dead macrophages again release DAMPs that again stimulate other macrophages nearby.
ischemia and autoimmunity [14,15,16]. As such, cell death-induced inflammation is a double-edged sword; it plays an important role in self-defense, but it can also be harmful to the host.
Necroptosis is another form of programmed cell death that is inflammatory. The microscopic features of necroptotic cells resemble cells that die from oncosis or necrosis in that widespread swelling of organelles occurs paired with the disruption of the plasma membrane, resulting in the release of cellular contents and an ensuing inflammatory response. The key molecules that drive necroptosis are receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1 and RIPK3) [24]. A recent study revealed the in vivo role of necroptosis in the host defensive response to vaccinia virus [25], and an analysis of RIPK3-deficient mice indicated the role of necroptosis in ischemic reperfusion injury in several organs [26]. Oncosis/necrosis
Oncotic necrosis is an inflammatory and non-programmed type of cell death characterized by organelle swelling and membrane rupture. Necrosis results from metabolic failure such as hypoxia or ischemia that coincides with the depletion of cellular ATP. In this type of cell death compromised lysosomes release their proteolytic contents into the cytosol, resulting in the destruction of the cell’s structure. In addition to metabolic deprivation, mechanical stress such as temperature or pressure can furthermore induce necrosis [2]. Pyroptosis
Inflammatory versus non-inflammatory cell death Apoptosis
Apoptosis, which is also called programmed cell death, occurs as a consequence of a sequence of well-characterized biochemical events [17]. A chief characteristic of apoptosis is the formation of a multimolecular signaling complex, the so-called apoptosome [18], leading to the activation of cysteine proteases (caspase-3/6/7) [19]. By contrast to other forms of cell deaths, membrane integrity is preserved while flipping of membrane lipids from the inner leaflet to the outer leaflet of the membrane to expose phosphatidylserine is one of the earliest events in apoptosis [20]. In addition, mitochondrial permeabilization [21] and DNA fragmentation occur during apoptosis [22]. As stated above, apoptosis is non-inflammatory as long as the integrity of the membrane is preserved. Upon induction of massive apoptosis, however, such as occurs in response to chemotherapy, processing of the apoptotic cells can be delayed, resulting in secondary necrosis [23]. There are several other known forms of programmed and non-programmed cell death that take place under pathological conditions. For example, necroptosis and pyroptosis are means of programmed cell Current Opinion in Immunology 2014, 30:91–98
Pyroptosis is another inflammatory type of programmed cell death that depends on the activation of caspase-1 [27] or caspase-11 [28] (caspase-5 in humans). The activation of caspase-1 takes place in a macromolecular complex called the inflammasome. Pyroptosis is inflammatory not just because it leads to the release of cellular contents through the disrupted plasma membrane, but because it leads to the release of interleukin (IL)-1alpha and the maturation of IL-1beta family cytokines. In addition, pyroptosis differs from apoptosis morphologically. Pyroptotic cells show an increase in volume and disruption of the plasma membrane without mitochondrial permeabilization. Still, DNA fragmentation occurs, similar to apoptosis [29]. In the context of host defense, the inflammasome is activated in response to many types of infection and toxins, from viruses to parasites. In addition, the inflammasome is activated by various non-infectious insults, including microcrystals or physical damage to the cell. Recent technological advances have highlighted the role of cellular metabolites in inflammasome activation; additionally, they have emphasized the role of the inflammasome in metabolic disorders, including obesity [30], diabetes [31], and atherosclerosis [32] (Table 1). www.sciencedirect.com
Inflammasome in response to cell death and metabolites Kono, Kimura and Latz 93
Inflammasome activation precedes pyroptotic cell death The molecular mechanisms of inflammasome activation are described elsewhere [33,34]. In brief, two distinct signaling pathways are required to activate the inflammasome: signal 1 and signal 2. Signal 1, which includes TLR ligands and cytokines, stimulates the transcription of inflammasome components, nucleotide-binding oligomerization domain-leucine-rich repeats containing pyrin domain proteins (NLRPs), and pro-cytokines. The components of signal 2 are diverse, ranging from monosodium urate crystal to ATP, and lead to assembly and activation of the inflammasome complex [35]. The inflammasome recruits and activates caspase-1, which then drives IL-1beta, IL-18, and IL-1alpha secretion [36]. Several types of inflammasomes have been described, but all contain the adaptor protein ASC, and formation is triggered by nucleotide oligomerization domain (NOD)-like receptors (NLRs), which are particular types of intracellular pattern recognition receptors that recognize pathogenassociated molecular patterns (PAMPs) and DAMPs [10,37]. For example, the NLRP inflammasome consists of NLRP3, the adaptor protein ASC, and caspase-1 [38], whereas the NLR family, caspase recruitment domain containing four (NLRC4) inflammasomes is formed upon the recognition of flagellin, an important constituent of Gram-negative bacterial flagella. NLRC4 also senses PrdJ, a component of the Gram-negative bacterial type III secretion system that facilitates infection by empowering the injection of bacterial proteins into host cells [39]. Finally, the NLRP3 inflammasome is formed in response to DAMPs and causes various types of damage to the cell itself, including the formation of pores in the plasma membrane and cell swelling [40]. Recently, cytosolic LPS was shown to be directly sensed inside of cells by caspase-4/5/11 that initiates non-canonical inflammasome activation [114]. Other than the maturation and secretion of IL-1 family cytokines, the inflammasome-induced activation of caspase-1 [27] and caspase-11 [28] initiates pyroptotic cell death. As stated above, pyroptosis is an inflammatory type of cell death that involves the secretion of pro-inflammatory cytokines and the exposure of hidden components within cells. The DAMPs of pyroptotic cells again are recognized by neighboring cells and initiate signal 1-mediated inflammasome activation. This vicious cycle of inflammasome
activation, pyroptotic cell death, and DAMP release is thought to be responsible for continuing non-infectious inflammatory processes such as atherosclerosis [32].
Molecular determinants of dead cells or metabolites activate the inflammasome Danger signals can be classified into two categories. The first includes molecules that are usually hidden inside cells but that are released when cells are injured and the integrity of the plasma membrane is lost. One example is high-mobility group B1 protein (HMGB1), which is a nuclear constituent that is loosely bound to chromatin and which is released into the extracellular space when cells die a necrotic cell death [41]. The second category includes molecules present in the extracellular matrix whose structure is revealed when the matrix is injured or broken. An example from this category is low molecular weight hyaluronan. Hyaluronan is a ubiquitously distributed extracellular matrix component that is broken down into lower molecular weight fragments when tissues are injured. Hyaluronan split products are recognized by TLR2 stimulating an inflammatory response [42]. In both categories, pattern recognition receptors (PRRs) recognize hidden molecules or structures that indicate injury to the body [6]. Most of the DAMPs identified so far are ubiquitous and abundant molecules that play important roles as constituents of cell or body structures. Thus, the DAMP-PRR system serves to recognize injury to the body. The ensuing innate immune activation prepares the host for a potential threat. The abundance and essentiality of DAMPs is analogous to PAMPs (e.g. lipid A or flagellin), which are abundant and indispensable molecules found in pathogens. Many molecules have been identified as DAMPs [6], and some have been shown to activate the inflammasome through either the signal 1 or signal 2 pathway. Here, we focus on those DAMPs that can be classified as metabolites (i.e. intermediates or final products of cellular and extracellular chemical reactions). When the body is under threat, increased unusual biochemical activity may increase the levels of specific metabolites, which the innate immune system can utilize to identify potential danger to the body. For example, it was recently shown that succinate enhances the transcription of IL-1beta. In response to LPS, macrophages utilize glycolysis more than oxidative phosphorylation, which generates succinate
Table 1 Mode of cell death and inflammation
Initiating Signaling pathway Terminal event Effect on tissue Cell types
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Apoptosis
Pyroptosis
Necroptosis
Programmed Caspase-3/6/7 Non-lytic Non-inflammatory All
Programmed Caspase-1 Lytic Inflammatory MP and DC
Programmed RIP1/3, PARP1 Lytic Inflammatory All
Oncosis/necrosis Accidental Non-caspase Lytic Inflammatory All
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[43]. These metabolites are also classified as extracellular versus intracellular metabolites (Table 2).
Uric acid for gout and tumor lysis syndrome Elevated serum levels of uric acid are the well-known cause of acute gouty arthritis, which is an inflammatory response to locally produced monosodium urate crystals. Uric acid was the first molecule to be identified as a danger signal released from dead cells. Initially, it was shown to activate dendritic cells and to facilitate CD8+ T cell responses to antigens associated with dead cells [44]. Later, uric acid was shown to induce acute neutrophil responses to dead cells [45]. Uric acid is a metabolite formed during the breakdown of purines (e.g. DNA, RNA, adenosine, and inosine). In humans but not in other mammals, uricase, which hydrolyzes uric acid to allantoin, is mutated resulting in an increased serum level of uric acid [46]. Uric acid is abundant inside cells, and is generated after cell death by the function of xanthine oxidase. The high concentration of uric acid at sites of cell death leads to the production of urate microcrystals, which act in inflammasome activation via the signal 2 inflammasome pathway [47]. Advances in chemotherapy and antibody engineering for the treatment of malignancies have made it possible to
eliminate a large number of target cancer cells instantly. The rapid destruction of malignancies causes cellular debris to flow into the bloodstream, resulting in tumor lysis syndrome. Specifically, there is a massive and abrupt release of intracellular metabolites, nucleic acid breakdown products, phosphorus, and potassium from chemosensitive tumor cells. Uric acid nucleates crystals when the level of urinary uric acid exceeds its solubility in the distal tubules and collecting ducts of the kidneys. This obstruction of the tubular lumen causes acute kidney injury [48].
Cholesterol, low-density lipoprotein (LDL), and atherosclerosis Excess blood cholesterol is a well-known risk factor for atherosclerosis. Over the last couple of decades, studies have shown that atherosclerosis is not just a disease of lipid deposition to the vascular wall, it is also a disease of chronic inflammation [49]. Furthermore, it has been shown that the NLRP3 inflammasome/IL-1 pathway contributes to atherogenesis by recognizing cholesterol crystals in situ. Mice deficient in NLRP3 inflammasome components in bone marrow-derived cells developed less atherosclerosis in an LDL receptor-deficient background [50]. Cholesterol crystals formed inside of foam cells in the vascular wall activate the inflammasome, leading to
Table 2 Metabolic danger signals and their relation to diseases Molecule Extracellular danger signal Cholesterol crystals Minimally modified LDL Glucose Islet amyloid polypeptide (IAPP) Uric acid
Receptor/effector
Inflammasome signal
Related pathological conditions
Reference
Phagolysosome rupture CD36, TLR4, micropinocytosis TXNIP Phagolysosome rupture, TLR2
Signal 2 Signals 1 and 2 Signal 2 Signals 1 and 2
Atherosclerosis Atherosclerosis Type 2 diabetes Type 2 diabetes
[32,50,59–62,63] [50,53,54,64–67] [31,57,68–72] [58,73–75]
Signals 1 and 2
Gout, tumor lysis syndrome, drug induced liver injury
[45,47,48,76–81]
Palmitate
TLR 2, TLR 4, CD14, cholesterol of plasma membrane, phagolysosome rupture TLR2, TLR4, NLRC4
Signals 1 and 2
Type 2 diabetes, Alzheimer’s disease
[55,82,83,84–89]
Intracellular danger signal Ceramide
CD38
Signal 2
[30,56,90–92]
NO
S-nitrosylation of NLRP3/caspase-1
Signal 2
Succinic acid ROS
HIF-1a, GPR91 TXNIP
Signal 1 Signal 2
Mevalonate metabolites
Rac, Rho
Signal 2
Insulin resistance, acute lung injury M. tuberculosis infection, sepsis, osteoarthritis, cerebrovascular disease Insulin resistance Various inflammation, insulin resistance, acute lung injury Interstitial lung disease, type 2 diabetes, mevalonate kinase deficiency
Current Opinion in Immunology 2014, 30:91–98
[93,94,95–101]
[43,102,103] [57,104–106]
[107,108,109–113]
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Inflammasome in response to cell death and metabolites Kono, Kimura and Latz 95
pyroptotic cell death [51]. Pyroptosis and the residing cholesterol crystals trigger inflammation. This vicious cycle may be the basis for the progress of atherosclerosis. It is well accepted that high serum levels of LDL play a major role in the initiation and progression of atherosclerosis. Atherosclerosis is initiated by the subendothelial retention of apolipoprotein B-containing lipoproteins [52]. The deposited LDL is modified by oxidative stress in the artery wall, which in turn is recognized by TLRs and scavenger receptors to transmit inflammatory signals and recruit monocytes [53]. Oxidized LDL has been shown to initiate the signal 1 pathway via NF-kB by ligating to CD14, CD36, TLR2, or TLR4 [54]. Oxidized LDL also promotes the signal 2 pathway when it is transported to the lysosomal compartment and converted into crystals [50,115].
Lipotoxic fatty acids, glucose, and islet amyloid polypeptide (IAPP) in diabetes Type 2 diabetes is characterized by insulin resistance with decreased insulin secretion from the pancreas, resulting in elevated levels of blood glucose. Serum levels of pro-inflammatory cytokines (e.g. TNF-alpha, IL-6, and IL-1) are increased in obesity-associated metabolic subjects [31]. Among them, IL-1 plays a major role in insulin resistance and inflammation-induced organ dysfunction in type 2 diabetes [116]. Wen et al. demonstrated that a lipotoxic fatty acid, palmitate, induced IL-1beta in mice fed a high-fat diet and subsequently altered insulin signaling [55]. Intracellular ceramide is also known to activate NLRP3 inflammasome formation and contributes to insulin resistance [56]. Chronic high levels of blood glucose also induce inflammasome activation in islet beta cells via increased mitochondrial reactive oxygen species (ROS) production and the dissociation of thioredoxin-interacting protein from thioredoxin [57]. In addition, the accumulation of high levels of IAPP activates the NLRP3 inflammasome in infiltrating pancreatic macrophages through the disruption of lysosomes and increased ROS production [58].
Acknowledgements This work is supported by a Grant-in-Aid for Scientific Research (B) and Grant-in-Aid for Challenging Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. HK is also supported by The Naito Foundation and a rheumatology research grant from Bristol-Myers Squibb. EL is supported by grants of the German Research Foundation (DFG), the National Institutes of Health (NIH) and he is a member of the ImmunoSensation Cluster of Excellence, the German Center for Infection Research (DZIF) and the Centre of Molecular Inflammation Research (CEMIR) at the Norwegian University of Science and Technology (NTNU).
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Future perspectives Unveiling the mechanism of inflammasome activation and its role in maintaining cell homeostasis will provide an important breakthrough in our understanding of chronic inflammatory diseases, including metabolic disorders. Not only pyroptosis but also necrosis precedes inflammasome activation via signals 1 and 2. However, our understanding of the vicious spiral of cell death and inflammasome activation is limited. In the near future, it will be essential to understand how inflammasome activation and cell death occur in vivo. However, these mechanistic studies should be interpreted in an integrated manner to reflect human pathophysiology. www.sciencedirect.com
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ScienceDirect Inflammasome activation in response to dead cells and their metabolites Hajime Kono1, Yoshitaka Kimura1,2 and Eicke Latz3,4,5 Cell death cannot go unnoticed. It demands that the surrounding cells clear away the corpses in a manner appropriate to the type of cell death. Dying cells represent a threat to the body that should be eliminated by the host immune response. Inflammasome activation followed by IL-1alpha release and IL-1beta maturation is crucial for tackling pathological conditions, including infections, whereas inflammasome activation precedes inflammatory pyroptotic cell death. On the other hand, recent studies have shown that the inflammasome plays an important role in the pathogenesis of metabolic diseases, including obesity, diabetes, and atherosclerosis. Here, we review current knowledge of the association between cell death, excess metabolites, and inflammasome activation as it relates to chronic inflammatory diseases. Addresses 1 Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan 2 Department of Allergy and Rheumatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan 3 Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany 4 Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA 5 German Center for Neurodegenerative Diseases, 53175 Bonn, Germany Corresponding author: Kono, Hajime ([email protected])
Current Opinion in Immunology 2014, 30:91–98 This review comes from a themed issue on Effects of endogenous immune stimulants Edited by Eicke Latz and Kensuke Miyake For a complete overview see the Issue and the Editorial http://dx.doi.org/10.1016/j.coi.2014.09.001 0952-7915/# 2014 Elsevier Ltd. All right reserved.
The way a cell dies matters more than the death itself Individual cells have a finite life span, and they are replaced with new ones after their demise. Only very few cell types last to the end of an individual’s lifetime. These long-lived cells include occipital neurons of the cerebral cortex, inner lens cells of the eyes, and muscle cells of the heart [1]. Moreover, the overall life span of cells varies by type. For example, intestinal epithelial cell www.sciencedirect.com
have an average life span of one day, while osteocytes can live for several years. At the end of a cell’s lifespan the cell usually dies from apoptosis. This form of cell death does not evoke an inflammatory response as it is part of the physiological cellular replacement which constantly occurs throughout life of multicellular organisms [2,3,4]. One of the most important factors determining whether cell death is inflammatory or not is the integrity of the plasma membrane [5,6]. If the plasma membrane integrity becomes compromised, hidden molecules inside cells — which are usually sequestered and not exposed to the extracellular milieu — are released. Some of these molecules exert pro-inflammatory activities in the extracellular space and are called damage-associated molecular patterns (DAMPs), or ‘danger signals’ [7,8]. In the early course of apoptosis the contents of the cell are not released and thus remain hidden from the extracellular environment. However, if apoptotic cells are not engulfed and cleared by adjacent cells or resident tissue macrophages in a timely manner, apoptotic cells become secondarily necrotic. In this situation, the integrity of the plasma membrane is lost and an inflammatory response is initiated [2]. Hence, apoptotic cells need to be recognized and their removal by the surrounding cells prevents an otherwise inflammatory reaction toward apoptosis (Figure 1). Once the plasma membrane has been damaged the DAMPs released from dead or dying cells can be recognized by local immune cells, such as macrophages or dendritic cells. Numerous innate immune signaling receptors can evoke inflammatory cascades toward DAMPs. In fact, most innate immune receptors, such as members of the Toll-like receptor (TLR) [9,10,11] or C-type lectin (CLR) families [12], that can recognize microbial substances can also respond to host derived danger signals. Hence our immune system is programmed to react to ourselves under certain situations. While at first sight counterintuitive, this mechanism could serve infection control against numerous kinds of pathogens [7,13]. With the limited sets germ-line encoded innate immune signaling receptors it may be challenging to recognize all types of pathogens. Mounting an inflammatory response to danger signals, which appear when the cellular integrity is perturbed by microbes or other means seems to be a feasible way of detecting invading microbes. In addition to a role of sensing cell death during infections, the inflammatory response to cell death also underlies the pathogenesis of many diseases in which cell death occurs in the absence of infection, including Current Opinion in Immunology 2014, 30:91–98
92 Effects of endogenous immune stimulants
Figure 1
death associated with distinct biochemical processes, similar to apoptosis. In comparison, cell death by oncosis and/or necrosis can occur accidentally without a defined biochemical process.
necrotic cell death
Necroptosis
DAMPs inflammasome activation
pyroptotic cell death
macrophage DAMPs inflammasome activation
IL-1 secretion macrophage
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Sequential inflammasome activation by necrosis and pyroptosis. Danger signals or DAMPs released from necrotic cells are recognized by macrophages in situ. Inflammasome-activated macrophages secrete IL1 family cytokines and fall in pyroptotic cell death. Pyroptotic dead macrophages again release DAMPs that again stimulate other macrophages nearby.
ischemia and autoimmunity [14,15,16]. As such, cell death-induced inflammation is a double-edged sword; it plays an important role in self-defense, but it can also be harmful to the host.
Necroptosis is another form of programmed cell death that is inflammatory. The microscopic features of necroptotic cells resemble cells that die from oncosis or necrosis in that widespread swelling of organelles occurs paired with the disruption of the plasma membrane, resulting in the release of cellular contents and an ensuing inflammatory response. The key molecules that drive necroptosis are receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1 and RIPK3) [24]. A recent study revealed the in vivo role of necroptosis in the host defensive response to vaccinia virus [25], and an analysis of RIPK3-deficient mice indicated the role of necroptosis in ischemic reperfusion injury in several organs [26]. Oncosis/necrosis
Oncotic necrosis is an inflammatory and non-programmed type of cell death characterized by organelle swelling and membrane rupture. Necrosis results from metabolic failure such as hypoxia or ischemia that coincides with the depletion of cellular ATP. In this type of cell death compromised lysosomes release their proteolytic contents into the cytosol, resulting in the destruction of the cell’s structure. In addition to metabolic deprivation, mechanical stress such as temperature or pressure can furthermore induce necrosis [2]. Pyroptosis
Inflammatory versus non-inflammatory cell death Apoptosis
Apoptosis, which is also called programmed cell death, occurs as a consequence of a sequence of well-characterized biochemical events [17]. A chief characteristic of apoptosis is the formation of a multimolecular signaling complex, the so-called apoptosome [18], leading to the activation of cysteine proteases (caspase-3/6/7) [19]. By contrast to other forms of cell deaths, membrane integrity is preserved while flipping of membrane lipids from the inner leaflet to the outer leaflet of the membrane to expose phosphatidylserine is one of the earliest events in apoptosis [20]. In addition, mitochondrial permeabilization [21] and DNA fragmentation occur during apoptosis [22]. As stated above, apoptosis is non-inflammatory as long as the integrity of the membrane is preserved. Upon induction of massive apoptosis, however, such as occurs in response to chemotherapy, processing of the apoptotic cells can be delayed, resulting in secondary necrosis [23]. There are several other known forms of programmed and non-programmed cell death that take place under pathological conditions. For example, necroptosis and pyroptosis are means of programmed cell Current Opinion in Immunology 2014, 30:91–98
Pyroptosis is another inflammatory type of programmed cell death that depends on the activation of caspase-1 [27] or caspase-11 [28] (caspase-5 in humans). The activation of caspase-1 takes place in a macromolecular complex called the inflammasome. Pyroptosis is inflammatory not just because it leads to the release of cellular contents through the disrupted plasma membrane, but because it leads to the release of interleukin (IL)-1alpha and the maturation of IL-1beta family cytokines. In addition, pyroptosis differs from apoptosis morphologically. Pyroptotic cells show an increase in volume and disruption of the plasma membrane without mitochondrial permeabilization. Still, DNA fragmentation occurs, similar to apoptosis [29]. In the context of host defense, the inflammasome is activated in response to many types of infection and toxins, from viruses to parasites. In addition, the inflammasome is activated by various non-infectious insults, including microcrystals or physical damage to the cell. Recent technological advances have highlighted the role of cellular metabolites in inflammasome activation; additionally, they have emphasized the role of the inflammasome in metabolic disorders, including obesity [30], diabetes [31], and atherosclerosis [32] (Table 1). www.sciencedirect.com
Inflammasome in response to cell death and metabolites Kono, Kimura and Latz 93
Inflammasome activation precedes pyroptotic cell death The molecular mechanisms of inflammasome activation are described elsewhere [33,34]. In brief, two distinct signaling pathways are required to activate the inflammasome: signal 1 and signal 2. Signal 1, which includes TLR ligands and cytokines, stimulates the transcription of inflammasome components, nucleotide-binding oligomerization domain-leucine-rich repeats containing pyrin domain proteins (NLRPs), and pro-cytokines. The components of signal 2 are diverse, ranging from monosodium urate crystal to ATP, and lead to assembly and activation of the inflammasome complex [35]. The inflammasome recruits and activates caspase-1, which then drives IL-1beta, IL-18, and IL-1alpha secretion [36]. Several types of inflammasomes have been described, but all contain the adaptor protein ASC, and formation is triggered by nucleotide oligomerization domain (NOD)-like receptors (NLRs), which are particular types of intracellular pattern recognition receptors that recognize pathogenassociated molecular patterns (PAMPs) and DAMPs [10,37]. For example, the NLRP inflammasome consists of NLRP3, the adaptor protein ASC, and caspase-1 [38], whereas the NLR family, caspase recruitment domain containing four (NLRC4) inflammasomes is formed upon the recognition of flagellin, an important constituent of Gram-negative bacterial flagella. NLRC4 also senses PrdJ, a component of the Gram-negative bacterial type III secretion system that facilitates infection by empowering the injection of bacterial proteins into host cells [39]. Finally, the NLRP3 inflammasome is formed in response to DAMPs and causes various types of damage to the cell itself, including the formation of pores in the plasma membrane and cell swelling [40]. Recently, cytosolic LPS was shown to be directly sensed inside of cells by caspase-4/5/11 that initiates non-canonical inflammasome activation [114]. Other than the maturation and secretion of IL-1 family cytokines, the inflammasome-induced activation of caspase-1 [27] and caspase-11 [28] initiates pyroptotic cell death. As stated above, pyroptosis is an inflammatory type of cell death that involves the secretion of pro-inflammatory cytokines and the exposure of hidden components within cells. The DAMPs of pyroptotic cells again are recognized by neighboring cells and initiate signal 1-mediated inflammasome activation. This vicious cycle of inflammasome
activation, pyroptotic cell death, and DAMP release is thought to be responsible for continuing non-infectious inflammatory processes such as atherosclerosis [32].
Molecular determinants of dead cells or metabolites activate the inflammasome Danger signals can be classified into two categories. The first includes molecules that are usually hidden inside cells but that are released when cells are injured and the integrity of the plasma membrane is lost. One example is high-mobility group B1 protein (HMGB1), which is a nuclear constituent that is loosely bound to chromatin and which is released into the extracellular space when cells die a necrotic cell death [41]. The second category includes molecules present in the extracellular matrix whose structure is revealed when the matrix is injured or broken. An example from this category is low molecular weight hyaluronan. Hyaluronan is a ubiquitously distributed extracellular matrix component that is broken down into lower molecular weight fragments when tissues are injured. Hyaluronan split products are recognized by TLR2 stimulating an inflammatory response [42]. In both categories, pattern recognition receptors (PRRs) recognize hidden molecules or structures that indicate injury to the body [6]. Most of the DAMPs identified so far are ubiquitous and abundant molecules that play important roles as constituents of cell or body structures. Thus, the DAMP-PRR system serves to recognize injury to the body. The ensuing innate immune activation prepares the host for a potential threat. The abundance and essentiality of DAMPs is analogous to PAMPs (e.g. lipid A or flagellin), which are abundant and indispensable molecules found in pathogens. Many molecules have been identified as DAMPs [6], and some have been shown to activate the inflammasome through either the signal 1 or signal 2 pathway. Here, we focus on those DAMPs that can be classified as metabolites (i.e. intermediates or final products of cellular and extracellular chemical reactions). When the body is under threat, increased unusual biochemical activity may increase the levels of specific metabolites, which the innate immune system can utilize to identify potential danger to the body. For example, it was recently shown that succinate enhances the transcription of IL-1beta. In response to LPS, macrophages utilize glycolysis more than oxidative phosphorylation, which generates succinate
Table 1 Mode of cell death and inflammation
Initiating Signaling pathway Terminal event Effect on tissue Cell types
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Apoptosis
Pyroptosis
Necroptosis
Programmed Caspase-3/6/7 Non-lytic Non-inflammatory All
Programmed Caspase-1 Lytic Inflammatory MP and DC
Programmed RIP1/3, PARP1 Lytic Inflammatory All
Oncosis/necrosis Accidental Non-caspase Lytic Inflammatory All
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[43]. These metabolites are also classified as extracellular versus intracellular metabolites (Table 2).
Uric acid for gout and tumor lysis syndrome Elevated serum levels of uric acid are the well-known cause of acute gouty arthritis, which is an inflammatory response to locally produced monosodium urate crystals. Uric acid was the first molecule to be identified as a danger signal released from dead cells. Initially, it was shown to activate dendritic cells and to facilitate CD8+ T cell responses to antigens associated with dead cells [44]. Later, uric acid was shown to induce acute neutrophil responses to dead cells [45]. Uric acid is a metabolite formed during the breakdown of purines (e.g. DNA, RNA, adenosine, and inosine). In humans but not in other mammals, uricase, which hydrolyzes uric acid to allantoin, is mutated resulting in an increased serum level of uric acid [46]. Uric acid is abundant inside cells, and is generated after cell death by the function of xanthine oxidase. The high concentration of uric acid at sites of cell death leads to the production of urate microcrystals, which act in inflammasome activation via the signal 2 inflammasome pathway [47]. Advances in chemotherapy and antibody engineering for the treatment of malignancies have made it possible to
eliminate a large number of target cancer cells instantly. The rapid destruction of malignancies causes cellular debris to flow into the bloodstream, resulting in tumor lysis syndrome. Specifically, there is a massive and abrupt release of intracellular metabolites, nucleic acid breakdown products, phosphorus, and potassium from chemosensitive tumor cells. Uric acid nucleates crystals when the level of urinary uric acid exceeds its solubility in the distal tubules and collecting ducts of the kidneys. This obstruction of the tubular lumen causes acute kidney injury [48].
Cholesterol, low-density lipoprotein (LDL), and atherosclerosis Excess blood cholesterol is a well-known risk factor for atherosclerosis. Over the last couple of decades, studies have shown that atherosclerosis is not just a disease of lipid deposition to the vascular wall, it is also a disease of chronic inflammation [49]. Furthermore, it has been shown that the NLRP3 inflammasome/IL-1 pathway contributes to atherogenesis by recognizing cholesterol crystals in situ. Mice deficient in NLRP3 inflammasome components in bone marrow-derived cells developed less atherosclerosis in an LDL receptor-deficient background [50]. Cholesterol crystals formed inside of foam cells in the vascular wall activate the inflammasome, leading to
Table 2 Metabolic danger signals and their relation to diseases Molecule Extracellular danger signal Cholesterol crystals Minimally modified LDL Glucose Islet amyloid polypeptide (IAPP) Uric acid
Receptor/effector
Inflammasome signal
Related pathological conditions
Reference
Phagolysosome rupture CD36, TLR4, micropinocytosis TXNIP Phagolysosome rupture, TLR2
Signal 2 Signals 1 and 2 Signal 2 Signals 1 and 2
Atherosclerosis Atherosclerosis Type 2 diabetes Type 2 diabetes
[32,50,59–62,63] [50,53,54,64–67] [31,57,68–72] [58,73–75]
Signals 1 and 2
Gout, tumor lysis syndrome, drug induced liver injury
[45,47,48,76–81]
Palmitate
TLR 2, TLR 4, CD14, cholesterol of plasma membrane, phagolysosome rupture TLR2, TLR4, NLRC4
Signals 1 and 2
Type 2 diabetes, Alzheimer’s disease
[55,82,83,84–89]
Intracellular danger signal Ceramide
CD38
Signal 2
[30,56,90–92]
NO
S-nitrosylation of NLRP3/caspase-1
Signal 2
Succinic acid ROS
HIF-1a, GPR91 TXNIP
Signal 1 Signal 2
Mevalonate metabolites
Rac, Rho
Signal 2
Insulin resistance, acute lung injury M. tuberculosis infection, sepsis, osteoarthritis, cerebrovascular disease Insulin resistance Various inflammation, insulin resistance, acute lung injury Interstitial lung disease, type 2 diabetes, mevalonate kinase deficiency
Current Opinion in Immunology 2014, 30:91–98
[93,94,95–101]
[43,102,103] [57,104–106]
[107,108,109–113]
www.sciencedirect.com
Inflammasome in response to cell death and metabolites Kono, Kimura and Latz 95
pyroptotic cell death [51]. Pyroptosis and the residing cholesterol crystals trigger inflammation. This vicious cycle may be the basis for the progress of atherosclerosis. It is well accepted that high serum levels of LDL play a major role in the initiation and progression of atherosclerosis. Atherosclerosis is initiated by the subendothelial retention of apolipoprotein B-containing lipoproteins [52]. The deposited LDL is modified by oxidative stress in the artery wall, which in turn is recognized by TLRs and scavenger receptors to transmit inflammatory signals and recruit monocytes [53]. Oxidized LDL has been shown to initiate the signal 1 pathway via NF-kB by ligating to CD14, CD36, TLR2, or TLR4 [54]. Oxidized LDL also promotes the signal 2 pathway when it is transported to the lysosomal compartment and converted into crystals [50,115].
Lipotoxic fatty acids, glucose, and islet amyloid polypeptide (IAPP) in diabetes Type 2 diabetes is characterized by insulin resistance with decreased insulin secretion from the pancreas, resulting in elevated levels of blood glucose. Serum levels of pro-inflammatory cytokines (e.g. TNF-alpha, IL-6, and IL-1) are increased in obesity-associated metabolic subjects [31]. Among them, IL-1 plays a major role in insulin resistance and inflammation-induced organ dysfunction in type 2 diabetes [116]. Wen et al. demonstrated that a lipotoxic fatty acid, palmitate, induced IL-1beta in mice fed a high-fat diet and subsequently altered insulin signaling [55]. Intracellular ceramide is also known to activate NLRP3 inflammasome formation and contributes to insulin resistance [56]. Chronic high levels of blood glucose also induce inflammasome activation in islet beta cells via increased mitochondrial reactive oxygen species (ROS) production and the dissociation of thioredoxin-interacting protein from thioredoxin [57]. In addition, the accumulation of high levels of IAPP activates the NLRP3 inflammasome in infiltrating pancreatic macrophages through the disruption of lysosomes and increased ROS production [58].
Acknowledgements This work is supported by a Grant-in-Aid for Scientific Research (B) and Grant-in-Aid for Challenging Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. HK is also supported by The Naito Foundation and a rheumatology research grant from Bristol-Myers Squibb. EL is supported by grants of the German Research Foundation (DFG), the National Institutes of Health (NIH) and he is a member of the ImmunoSensation Cluster of Excellence, the German Center for Infection Research (DZIF) and the Centre of Molecular Inflammation Research (CEMIR) at the Norwegian University of Science and Technology (NTNU).
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