Over the last decade, danger-associated molecular pattern molecules, or alarmins, have been recognized as signaling mediators of sterile inflammatory responses after trauma and injury. In contrast with the accepted passive release models suggested by the “danger hypothesis,” it was recently shown that alarmins can also directly sense and report damage by signaling to the environment when released from live cells undergoing physiological stress, even without loss of subcellular compartmentalization. In this article, we review the involvement of alarmins such as IL-1α, IL-33, IL-16, and high-mobility group box 1 in cellular and physiological stress, and suggest a novel activity of these molecules as central initiators of sterile inflammation in response to nonlethal stress, a function we denote “stressorins.” We highlight the role of posttranslational modifications of stressorins as key regulators of their activity and propose that targeted inhibition of stressorins or their modifiers could serve as attractive new anti-inflammatory treatments for a broad range of diseases.

The cellular host immune response against pathogens requires viral or microbial recognition by the immune system oriented toward the prevention, control, and resistance to infectious diseases. Pathogen components, commonly termed pathogen-associated molecular patterns (PAMPs), activate immune cells that discriminate self from nonself and promote the function of APCs, or tissue-associated phagocytosis mediated via PAMP receptors such as the TLRs. Upon activation, cells induce the expression of chemokines, as well as the active secretion of proinflammatory cytokines, which involves several transport pathways including direct transport to the cell surface, or routing through recycling endosomes or the phagocytic cup (reviewed in Ref. 1).

When injury or organ damage occur, or are triggered by physical, chemical, or metabolic assault, cells die by necrosis, and rupture and lose their integrity in a sterile environment without the involvement of pathogens (2). This type of traumatic cell death also induces the recruitment of inflammatory cells to the site of injury and results in a massive immune response triggered by recognition of such danger or alarm signals (3).

Indeed, years ago, when the danger-associated molecular patterns (DAMPs) and the danger model were introduced, this model predicted that intracellular factors, which normally reside within cells, would be exposed and become available for recognition by the immune system at the time of necrotic cell death, when cells lose their compartmentalization. Those cellular factors are released into the microenvironment and thereby trigger inflammation (4, 5). Over the years, several sterile stimuli that include cell components and endogenous DAMPs such as DNA, RNA, ATP, and others (3, 6) were found to be recognized by the same host-pathogen recognition receptors that are also used for the recognition of PAMPs. Despite the fact that this process is sterile, activation of these receptors by DAMPS typically leads to upregulation of the same proinflammatory cytokines and chemokines as those activated after PAMP recognition, including IL-1β or IL-6, which further activate or amplify the inflammatory signal.

In addition, another subset of intracellular proteins is passively released from dying necrotic cells and was found to mediate sterile inflammatory processes. These proteins include several members of the IL-1 family such as IL-1α (7), IL-33 (8, 9) and high-mobility group box 1 (HMGB1) (10); these molecules typically exhibit dual functionality, serving as cytokines as well as performing yet mostly uncharacterized nuclear functions. In contrast with the variety of DAMPs that are recognized by the general PAMP receptors like TLRs, activation of dual-function protein signaling pathways occurs via ligation to specific downstream receptors, such as the IL-1R and the IL-33 ST2 receptor (or IL-1R-like 1), which are highly expressed on Th2 and mast cells, or the receptor for advanced glycation end products that binds HMGB1 and results in neutrophil and macrophage recruitment to the site of injury.

As expected, HMGB1, IL-1α, IL-33, and IL-16 (also considered a dual-function cytokine) (1114) share overall structural and sequence similarities (Fig. 1). For example, the N-terminal side of the proteins generally contains a DNA or chromatin-binding domain (7, 1416), several protease cleavage sites (reviewed in Ref. 17) that segregate the intracellular activity and cellular localization (7, 18, 19), or regulate cytokine activity (2022) by enhancing receptor binding through the receptor-interacting domains located in the C-terminal part of the proteins. Under normal homeostatic conditions, these proteins are constitutively expressed in many cell types; they are mainly targeted to the cell nucleus (9, 2326) as biologically active precursors, which do not need further processing, and are ready to promote inflammation immediately upon release when cell necrosis occurs. Interestingly, for both HMGB1 and IL-1α, a mechanism restricting their release during apoptosis was described (6, 9), ensuring the differential release of alarmins only during necrosis and not apoptosis, which takes place under normal cell turnover and does not require the induction of a sterile inflammatory response.

FIGURE 1.

Dual-function cytokines share structural similarities. Schematic representation of the most extensively studied dual-function cytokines, typically containing a large N-terminal tail, possessing the chromatin or DNA-binding domains (red), and including NLSs (blue), which enable their intracellular nuclear function. Most of the dual-function proteins are naturally synthesized as active precursor proteins, with the receptor-interacting domains located in their C-terminal side (green). During traumatic cell death, immediate release occurs after necrosis, enabling instant alarm or danger signaling without the need for further processing or modification. To produce the highly active mature cytokines and facilitate active secretion by immune cells, the precursor proteins are processed and cleaved by several innate immune cell proteases (position of cleavage sites are marked by black lines) including calpain; granzyme B (GzmB); the basophil and mast cell protease, chymase; neutrophil elastase (NE); the inflammasome caspase-1, or the apoptotic-related caspase-3/7; neutrophil proteinase 3 (PR3); and neutrophil cathepsin G (CathG).

FIGURE 1.

Dual-function cytokines share structural similarities. Schematic representation of the most extensively studied dual-function cytokines, typically containing a large N-terminal tail, possessing the chromatin or DNA-binding domains (red), and including NLSs (blue), which enable their intracellular nuclear function. Most of the dual-function proteins are naturally synthesized as active precursor proteins, with the receptor-interacting domains located in their C-terminal side (green). During traumatic cell death, immediate release occurs after necrosis, enabling instant alarm or danger signaling without the need for further processing or modification. To produce the highly active mature cytokines and facilitate active secretion by immune cells, the precursor proteins are processed and cleaved by several innate immune cell proteases (position of cleavage sites are marked by black lines) including calpain; granzyme B (GzmB); the basophil and mast cell protease, chymase; neutrophil elastase (NE); the inflammasome caspase-1, or the apoptotic-related caspase-3/7; neutrophil proteinase 3 (PR3); and neutrophil cathepsin G (CathG).

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Recently, several lines of evidence suggested that dual-function proteins could also be released under several physiological stress conditions that are not associated with necrotic cell death and loss of plasma membrane integrity (Fig. 2). In addition, we found that IL-1α can report the presence of chromatin damage from the nucleus back to the surrounding tissue by directly sensing DNA damage after its recruitment to damage sites (23). Although the traditional danger model postulates passive release of alarmins by dying cells, we suggest that alarmins can also directly and actively sense and report stress in cells that are not moribund (Fig. 2). Thus, although cytokines are actively secreted in response to infection by pathogens and PAMP recognition, and alarmins represent passive release of danger signaling after traumatic cell death or injury, we suggest that the term stressorin be used for factors actively released in response to stress (Fig. 2). Considering the wide range of factors that affect stressorin secretion or release, we believe that each designated environmental stress signaling pathway is likely followed by a distinctive pattern of stressorin release to achieve its unique function and promote the desirable downstream inflammatory signaling and physiological outcome. Thus, stress sensing and stressorin release in response to numerous physiological and cellular stress conditions, including genotoxic DNA damage, UV light, heat shock, or oxidative stress damage, can actively contribute to extracellular stress signaling into the microenvironment and can support its resolution and tissue recovery. Nevertheless, when extended stimulation or hypercellular stress signaling occurs, it can lead to constant release of stressorins and ongoing systemic danger signaling that may thereby activate massive continuous, systemic chronic inflammation. Furthermore, it seems that chromatin may not solely serve as a platform for sensing damaged or fragmented DNA by alarmins, but also as a mechanistic switch, which regulates inflammation and stressorin release by facilitating their interactions with chromatin-modifying enzymes, leading to their modification and further priming them for secretion.

FIGURE 2.

Nomenclature and differences between cytokine and alarmin activities in injury release and stress secretion. (A) Cytokines are secreted by innate immune cells in an active process after pathogens stimulate PAMP receptors and induce their de novo synthesis, cytoplasmic translocation, and usually, protease cleavage and maturation. (B) Dual-function proteins (alarmins) are constitutively expressed in somatic cells and are passively and rapidly released during primary necrosis when cells lose their plasma membrane integrity and compartmentalization. Commonly, upon apoptosis, dual-function alarmins are retained by the nucleus or inactivated by apoptotic-related caspases such as caspase-3/7, abrogating sterile inflammation signaling. Apoptotic bodies or secondary necrosis can ultimately lead to the release of alarmins and stimulation of limited sterile inflammation. (C) Stressorins, in contrast with cytokines, do not require receptor stimulation or de novo synthesis and can likely actively sense damage via PTMs. Similar to cytokines, but in contrast with alarmins, they are most likely actively secreted by somatic cells, but require no additional processing by specific innate immune cell proteases and signal in a manner similar to alarmins.

FIGURE 2.

Nomenclature and differences between cytokine and alarmin activities in injury release and stress secretion. (A) Cytokines are secreted by innate immune cells in an active process after pathogens stimulate PAMP receptors and induce their de novo synthesis, cytoplasmic translocation, and usually, protease cleavage and maturation. (B) Dual-function proteins (alarmins) are constitutively expressed in somatic cells and are passively and rapidly released during primary necrosis when cells lose their plasma membrane integrity and compartmentalization. Commonly, upon apoptosis, dual-function alarmins are retained by the nucleus or inactivated by apoptotic-related caspases such as caspase-3/7, abrogating sterile inflammation signaling. Apoptotic bodies or secondary necrosis can ultimately lead to the release of alarmins and stimulation of limited sterile inflammation. (C) Stressorins, in contrast with cytokines, do not require receptor stimulation or de novo synthesis and can likely actively sense damage via PTMs. Similar to cytokines, but in contrast with alarmins, they are most likely actively secreted by somatic cells, but require no additional processing by specific innate immune cell proteases and signal in a manner similar to alarmins.

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In this review, we describe the activity and release of dual-function proteins or stressorins in response to stress stimuli. In addition, we suggest that their mode of action, their regulation, and release under such conditions should be considered as possible future therapeutic pathways when chronic stress signaling occurs, driving systemic low-grade inflammation.

Chemical and genotoxic stresses.

Cells that undergo physiological stress frequently induce recruitment of inflammatory cells, resulting in sterile inflammation. In this review, we suggest that stressorins play a central role in such processes after their release, to promote wound healing and repair, tissue regeneration, or cellular recovery from physiological stress.

In support of this notion, it was shown that numerous environmental pollutants, including cigarette smoke (27, 28) or hydrocarbon oil (29), which most likely do not lead to cell necrosis, induce IL-1α–dependent inflammation and neutrophil infiltration. Cigarette smoke also alters the lung microenvironment to facilitate an alternative IL-33–dependent exaggerated proinflammatory response to infection, exacerbating disease (30). In addition, upon chemical stress induced by toxins, or chemotherapy with genotoxic or alkylating agents, cells were shown to release DAMPs. Treatment with oxaliplatin and/or 5-fluorouracil promoted the release of HMGB1 and heat shock protein 70 from cells, leading to dendritic cell maturation via TLR4-dependent activation (31). Bleomycin and etoposide (VP-16) lead to massive secretion of IL-1α from human fibrosarcoma and keratinocytes without any evidence of necrosis (23). These findings collectively suggest that DAMP release from chemical- or drug-treated cells apparently plays a vital role in immune cell maturation and in activating a stress-related immune response (23).

Metabolic stresses.

In recent years, a large number of studies showed a close link between metabolism and immunity. It is now clear that in diseases such as diabetes, obesity, anorexia, or other metabolic syndromes associated with abnormal metabolic homeostasis, a state of chronic low-level inflammation can be seen (32). Moreover, it was recently found that sustained inflammation could also work in a reverse direction and alter glucose homeostasis (33). Recently, the stressorin activity of IL-1α during metabolic stress was also highlighted as an inducer of IL-1α–dependent sterile inflammation in atherosclerosis. Fatty acids were identified as potent inducers of IL-1α–driven vascular inflammation and shown to selectively stimulate the release of IL-1α, but not of IL-1β, by uncoupling mitochondrial respiration. Moreover, it was shown that fatty acid–induced mitochondrial uncoupling abrogated IL-1β secretion and deviated the response elicited by cholesterol crystals toward selective production of IL-1α (34). Similarly, IL-1α together with other proinflammatory cytokines like IL-6 are dramatically elevated in hyperglycemic children with type 1 diabetes mellitus even after return to euglycemia, whereas levels of the other cytokines like IL-1β, IL-10, IL-15, or TNF-α remain normal, suggesting that its stressorin signaling also occurs after glycemic stress is resolved (35). Likewise, patients with metabolic syndrome, which is associated with a proinflammatory milieu and accounts for increased cardiovascular risk, exhibit alterations in their blood cytokine and growth factor profiles, with IFN-γ and IL-1α identified as the most significant independent biomarkers elevated in the patients’ serum (36). Furthermore, it was also proposed that IL-1α secreted from adipose tissue may have a critical function in the development of obesity and could contribute to its associated morbidity (37). In addition, serum levels of the energy balance hormone, leptin, increase in humans after administration of recombinant human IL-1α (38), and animals implanted with MCF-7 breast cancer cells overexpressing the secreted form of IL-1α became cachectic, and their serum leptin levels are correlated with levels of IL-1α, but not with other known cachexia-inducing cytokines, such as IL-6, TNF, or IFN-γ. The effect was specific for IL-1α–expressing tumor cells, suggesting that IL-1α increases leptin expression in stromal cells recruited into the tumor microenvironment (39). Correspondingly, IL-1α–deficient mice fail to induce leptin expression in skin tissue after UV exposure (23), suggesting that serum IL-1α may cause cachexia by affecting leptin-dependent metabolic pathways. In contrast, persistent DNA damage signaling triggers a chronic autoinflammatory response followed by release of HMGB1 and infiltration of activated macrophages, leading to fat depletion (40).

Remarkably, HMGB1 also shows a substantial link with metabolic stress signaling and metabolism. HMGB1 knockout mice die shortly after birth with severe hypoglycemia (41), and this cytokine was also found to be a critical regulator of mitochondrial function (42). Adipose tissue was also shown to secrete HMGB1 in response to inflammatory signals characterizing obesity (43), and HMGB1 expression and release by human adipocytes is altered by inflammatory conditions imposed by obesity and insulin resistance (44). In addition, HMGB1 also seems to play an important role in the inflammatory process associated with childhood obesity, and was suggested as a diagnostic marker for obesity-related metabolic syndrome (45). Above all, both IL-1α and HMGB1 can control leptin (46) and weight loss (47), respectively.

These findings strongly support the possible link between the cellular response to metabolic stress and innate inflammation mediated by stressorins. A growing body of evidence indicates a relationship between chronic inflammation and the disruption of cellular metabolism, suggesting that perhaps DAMPs, rather than classical cytokines like IL-1β, IL-6, or TNF-α, should be followed, and possibly also targeted, in patients with metabolic disorders and diseases. Accordingly, a recent new promising treatment using neutralizing Abs targeting HMGB1 reduced weight gain in mice fed a high-fat diet (47). Likewise, neutralizing IL-1α using a mAb (MABp1) in colorectal cancer patients reduced systemic inflammation and fatigue, and led to gain of lean body mass associated with increased survival. This emphasizes the potential of inhibition of dual-function cytokines as a new approach in treating systemic inflammation in a range of diseases associated with chronic stress signaling (48, 49).

Oxidative and genotoxic stresses.

Oxidative stress occurs when cells fail to restrain, control, or neutralize the toxicity of reactive oxygen species (ROS). This usually results in wide-ranging cellular oxidative damage to many cell components including proteins, lipids, and DNA. ROS generated by metabolism can also cause substantial DNA base damage along with dsDNA breaks and lesions, affecting DNA replication and mutagenicity, which may contribute to tumorigenesis and carcinogenesis (50). The link between inflammation and oxidative stress is well established, and both these processes are associated with the progression and pathogenesis of cancer and numerous inflammatory diseases (51). Cancer and inflammatory cells were shown to produce free radicals and soluble mediators, such as metabolites of arachidonic acid, cytokines, and chemokines, which act by further inducing ROS. These in turn strongly recruit additional inflammatory cells in a vicious cycle (52). Thus, in several autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, chronic inflammation and hence oxidative stress were closely associated with disease progression. It is no surprise that oxidative stress and ROS were also shown to play a fundamental role in the regulation of alarmins or stressorins. Despite the fact that the mechanisms that contribute to HMGB1 activity have not been fully resolved (53), it appears that oxidative stress is a central regulator of HMGB1 translocation, release, and activity in sterile inflammation and after cell death (54). HMGB1 undergoes reversible oxidative modifications at cysteine residues during cell death, which modulates its biological properties. Oxidation of HMGB1 attenuates its proinflammatory activity (55), particularly during apoptosis (56), when induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of the protein (57) to eliminate danger signaling (58). UV exposure (which likely induces photo-oxidative damage by UV-induced ROS and not necrosis) seems to stimulate HMGB1 release by keratinocytes (59) or conjunctival epithelial cells as a stressorin (60). In addition, it was also reported that UV irradiation induces a TLR4/MYD88-driven neutrophilic skin inflammatory response in animal models initiated by HMGB1 release from damaged keratinocytes (61). Most importantly, ROS quenchers can decrease HMGB1 release after UV stimulation (60), suggesting that it may have active stress-sensing capacities and signaling functions similar to IL-1α stressorin activity. Oxidation of IL-33 was also demonstrated to regulate its activity in ST2 receptor–dependent inflammation. The biological activity of IL-33 at its receptor is rapidly terminated by formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site (62). Although it was clearly demonstrated that free cysteines control the conformational switch for IL-33 and possibly other IL-1 family members, the closely related IL-1α does not respond to the same oxidation switch, or show any susceptibility to oxidation state.

In contrast with HMGB-1 and IL-33, which undergo oxidative inactivation, IL-1α appears to be secreted as a cytokine or stressorin and to remain active in an oxidative environment. Senescence-associated shifts in steady-state H2O2 and intracellular Ca2+ levels cause an increase in IL-1α expression and processing of the cytokine to its highly active mature form (63). In keratinocytes that express high levels of IL-1α (64), exposure to UV irradiation results in increased IL-1α expression and release (65). The expression and nuclear localization of IL-1α appear to also be redox dependent, whereby shifts in steady-state H2O2 concentrations resulting from enforced expression of manganese superoxide dismutase drive IL-1α mRNA and protein expression (66). Ozone-exposed macrophages induce an alveolar epithelial chemokine response through IL-1α release as a stressorin, which stimulates alveolar epithelial cells to further secrete chemokines, together with a strong sterile inflammatory response (67). Neutralizing Abs for IL-1α, but not Abs targeting IL-1β, repress chemokine secretion by these alveolar epithelial cells. Accordingly, deficiency of the leukocyte NADP (NADPH) oxidase, an enzyme-producing ROS important for microbial elimination and regulation of inflammation, enhances the early local release of IL-1α and controls the neutrophilic response to sterile inflammation in mice (68). Furthermore, under hypoxic stress, ROS formation may be induced as cells try to rapidly adjust to the changes in oxygen availability and the substantial metabolic stress. Under these conditions, the transcriptome is rapidly altered and usually includes induction of proangiogenic and proinflammatory genes. Hypoxia is often associated with increased ROS generation and stabilization of hypoxia-induced factors (HIFs) (69). The HIFs are master transcriptional regulators of cellular response to hypoxia, and they were shown to take part in IL-1α transcription upregulation under hypoxic conditions. IL-1α transcription can be either restrained or induced by HIF-1α and HIF-2α factors during hypoxia, depending on the cell type (70). Altogether, we suggest that under different selected stress conditions, a given stressorin is released and others will be regulated (e.g., cleaved or inactivated) to achieve a particular inflammatory and cellular response.

The majority of the eukaryotic secreted proteins are released via the conventional endoplasmic reticulum–Golgi secretory pathway. However, some nuclear proteins or proteins lacking a signal peptide were shown be secreted by nonconventional routes (1). Because this nonconventional mechanism is still poorly understood, and all stressorins discussed earlier are secreted by this enigmatic pathway, it remains to be determined whether, how, and when active secretion or passive release by cells that maintain their integrity takes place (71, 72). In addition, it should be remembered that these stressorins can be actively or passively released in response to many types of stimuli, including PAMPs and DAMPs or, in some cases, the combination of multiple stimuli, when their release can be influenced by type of stimulus, its strength, and the type of cell releasing it.

Protein posttranslational modifications (PTMs) are involved in the regulation of almost all cellular processes. They allow rapid control and alteration in protein functions, leading to their relocalization, trafficking, activation/inactivation, or regulation of protein–protein interactions and assembly into functional specialized complexes. Stress responses are also governed by PTMs, which were shown to regulate DNA damage (73), genotoxic stresses (74), apoptosis (75), heat shock (76), oxidative stress (77), and hypoxic stress responses (78). In particular, PTMs control the assembly of stress granules (79), and they were recently also demonstrated to play a major role in protein secretion (80). Therefore, we propose that PTMs and their modifying enzymes play a central role in regulating stressorin translocation, release, and inactivation, and may contribute to stress sensing through redirection and integration of those proteins into stress granules, or facilitating their intracellular interactions.

Indeed, it appears that one major step of controlling sterile inflammation induced by stressorins is through regulation of their nuclear cytoplasmic shuttling, a process commonly regulated by PTMs (81). When dual-function cytokines are targeted to the nucleus or redirected to the cytoplasm by mutations or deletions of their nuclear localization sequence (NLS), their secretion or release can be attenuated or, alternatively, enhanced. For example, altered subcellular localization of IL-33 (e.g., by abolishing the NLS) leads to nonresolving lethal inflammation after massive systemic secretion of the cytokine (19). Likewise, the expression of nuclear localized IL-1α was reported to cause multiple (and, at times, contradictory) outcomes including impaired cell growth (82), oncogenic transformation (83), changes in human endothelial cell migration (84), and apoptosis of cancer cells (85); nevertheless, such nuclear localization also contributes to its retention by cells, whereas its release is significantly elevated when expressed as a cytosolic protein (18). For HMGB1 as well, the first critical step in the protein release from activated immune cells is its mobilization from the nucleus to the cytoplasm (86, 87).

In fact, in the case of both IL-1α (23) and HMGB1 (86), acetylation of the NLS seems to regulate the nuclear/cytoplasmic localization of the dual-function cytokines, and ultimately their release. IL-1α is acetylated within the first lysine of its NLS and remains nuclear. Upon DNA damage, IL-1α acetylation is removed by histone deacetylase-1 (HDAC-1) and results in cytoplasmic shuttling followed by secretion. Interestingly, HDAC inhibitors, which lead to hyperacetylation of IL-1α and decrease its secretion, are widely used as anti-inflammatory drugs and are approved for treatment of several diseases. In contrast, cells hyperacetylate HMGB1 to redirect it toward secretion, and the JAK/STAT1 signaling pathway (also mediating other cellular stress responses caused by hypoxia/reperfusion, endotoxin, UV light, and hyperosmolality) (reviewed in Ref. 88) participates in its nuclear translocation by mediating this hyperacetylation response (86, 87). Similar to IL-1α, which interacts with HDAC-1, the silent mating type information regulation 2 homolog (Sirtuin-1 or SIRT1), a known NAD-dependent deacetylase, which is involved in cellular senescence and possibly the response to inflammation, was shown to form a stable complex with HMGB1. SIRT1 inhibits HMGB1 release via its N-terminal lysine residues and improves survival in a sepsis model. Activation by inflammatory stimuli promotes HMGB1 release by inducing its dissociation from SIRT1, in an acetylation-dependent manner, whereas in vivo infection with wild-type SIRT1 and a hypoacetylated HMGB1 mutant improved survival (85.7%) during endotoxemia, indicating that the acetylation-dependent interaction between HMGB1 and SIRT1 is apparently critical for LPS-induced lethality (89). Because stress sensing and modification by different master regulators of stress may be required for immune stress signaling, we predict that the regulation of stressorins will not be dependent on a single mechanism, but on numerous pathways to control and regulate secretion under stress.

Indeed, several different PTMs and modifiers were shown to regulate HMGB1 release from different cell types and/or under diverse conditions. For instance, phosphorylation within its NLS regions, most likely by protein kinase C ζ (90), was also shown to contribute to its dynamic nucleocytoplasmic shuttling, and redirects the cytokine toward secretion (91). Posttranslational monomethylation of HMGB1 at Lys42 (92) or Lys112 (93) results in loose binding to DNA and translocation to the cytoplasm in neutrophils or in clear cell renal cell carcinoma. Although insufficient by itself, PARP-1 activation and HMGB1 PARylation also lead to translocation from the nucleus to the cytoplasm by upregulating HMGB1 NLS hyperacetylation. Besides facilitating its subsequent acetylation, HMGB1 PARylation is also suggested to increase the activity ratio of histone acetyltransferases to HDACs on the HMGB1 NLS (94). In addition, N-linked glycosylation plays a crucial role in the secretion of HMGB1. Several residues were found to be N-glycosylated in HMGB including N37, N134, and the nonconsensus residue, N135, whereas nonglycosylated double-mutant proteins HMGB1N37Q/N134Q and HMGB1N37Q/N135Q showed localization to the nucleus, strong binding to DNA, weak binding to the nuclear export protein, chromosomal maintenance 1 (CRM1 or Exportin1), and rapid degradation by ubiquitylation. These mutant proteins had reduced secretion even after acetylation, phosphorylation, oxidation, and exposure to proinflammatory stimuli (95). Altogether, it seems that HMGB1 intracellular localization and nuclear/cytoplasm shuttling is highly regulated by diverse PTMs mediated by several stress-related modifiers that govern its release.

The precursor form of IL-16, which is released by a variety of cells including lymphocytes and epithelial cells, and acts as a chemoattractant for certain immune cells, is phosphorylated on Ser144 by MAPKs in activated T lymphocytes (96). The precursor of IL-1α is also modified by phosphorylation at the end of its NLS on residue Ser90 (97, 98), which was suggested to affect the association with membrane proteins and cellular transport. Interestingly, human IL-1α precursor was found to be myristoylated by an unidentified lysyl ε-amino N-myristoyl-transferase that was proposed to facilitate its specific membrane targeting (99). The SIRT6 enzyme, which was initially considered only as a NAD-dependent deacetylase and was implicated in regulation of transcription, genome stability, metabolism, and regulation of life span, was recently and surprisingly shown to remove long-chain myristoyl groups and promote TNF-α secretion by removing its fatty acyl modifications (100). Such activity could also be responsible for the regulation of IL-1α acylation and may play a role in its nonclassical protein release or secretion.

Alarmins and stressorins communicate with the immune system as danger signals when the tissue is under attack. The innate response, especially that of the neutrophils and macrophages, can involve phagocytosis of dead cells or promotion of tissue repair, but can also provoke an extensive inflammatory response. Continuous and chronic immune danger signaling or nonresolved inflammation may contribute to pathologies, including chronic obstructive pulmonary disease, such as asthma or emphysema, inflammatory bowel disease, multiple sclerosis, obesity, arthritis, or rheumatic diseases (101). Even allergies were proposed to be initiated by direct cell damage through toxic chemicals and allergenic proteases, and are most probably mediated by stressorins as well (102). Most importantly, endogenous alarmins and stressorins can promote cancer development and progression; for example, UV-induced chronic inflammation and stress signaling were shown to promote angiogenesis and metastasis in melanoma (61).

Looking at the broad range of environmental and physiological signals that may lead to inflammation, the spectrum and potential of neutralizing stressorins in diseases seems to be extremely wide. Although the extent of their involvement as stress signals has only now come to light, we should expect the discovery of novel stress signaling molecules and stressorins, and the demonstration of their major contribution to disease progression, symptoms, and prognosis in a broad range of diseases with active raging inflammation. It is thus no wonder that the bioactivity of the less familiar alarmin, IL-16, has been recently closely associated with the progression of a number of different cancers and rheumatic diseases (103). Tissue expression and serum levels of IL-16 increase in association with malignant ovarian tumor development and progression (104), and serum proteomic analysis identified IL-16 as a biomarker for clinical response during early treatment of rheumatoid arthritis (105). In addition, it was also recently proposed that IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Hence, it was hypothesized that IL-15 normally contributes to tissue protection by supporting the elimination of infected cells, but when its expression is chronically dysregulated it can promote the development of complex T cell–mediated disorders associated with tissue destruction, such as celiac disease and type 1 diabetes (106).

Although the reports of novel alarmins or stressorins and their function in immune activation are rapidly on the rise, uncovering the full potential of their inhibition as a new therapeutic approach will require extensive study of the intracellular pathways leading to their release and inactivation under different physiological conditions, and testing their involvement in a spectrum of diseases that are not classically considered as inflammatory, including depression (107111), anorexia (38, 46), Alzheimer’s disease (112, 113), or even migraine and headache (114) in which stressorins appear to play a role. Further studies are needed to clarify the possible conflicting roles of stressorin signaling when they may exhibit damaging (as mediators of systemic inflammation) or beneficial (as drivers of tissue repair and organ regeneration) properties within the same disease condition. Nevertheless, the recent identification of stressorin release in response to cellular stress constitutes a new and exciting therapeutic strategy to target and reduce inflammation in chronic pathologies, and may serve as a novel potential diagnostic biomarker. Therefore, a systematic understanding of alarmin/stressorin processing and release or secretion is crucial to classify and characterize their biological roles and their contributions to a variety of inflammatory and autoimmune diseases.

We thank Dr. Shelley Schwarzbaum for scientific editing and critical reading of the manuscript.

This work was supported by the Ministry of Aliya and Immigrant Asorption (I.C.); the Center for Absorption in Science, Israel (I.C.); the Israel Ministry of Science jointly with the Deutsches Krebsforschungscentrum, Heidelberg, Germany (R.N.A. and E.V.); the Israel Science Foundation supported by the Israel Academy of Sciences and Humanities (R.N.A. and E.V.); the Israel Cancer Association and the Israel Ministry of Health Chief Scientist’s Office, 7th Framework Programme for Research and Technological Development: Cancer Inflammation (INFLA-CARE) (R.N.A. and E.V.); the Binational (Israel) Science Foundation (R.N.A. and E.V.); and the German-Israeli Foundation (R.N.A. and E.V.).

Abbreviations used in this article:

     
  • DAMP

    danger-associated molecular pattern

  •  
  • HDAC

    histone deacetylase

  •  
  • HIF

    hypoxia-induced factor

  •  
  • HMGB1

    high-mobility group box 1

  •  
  • NLS

    nuclear localization sequence

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • PTM

    translational modification

  •  
  • ROS

    reactive oxygen species.

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The authors have no financial conflicts of interest.