Introduction
Traumatic injury, a major contributor to worldwide mortality, is one of the world’s most relevant but neglected health concerns [
1,
2]. Next to the severe injury itself, which often results in immediate or early death at the scene or within only of a few hours, in the later post-injury phase, a large number of trauma patients die due to inflammation-related post-injury complications, which affect the immune system homeostasis, ending up in e.g., sepsis, septic shock, or multiple organ dysfunction syndrome (MODS) [
2‐
6]. For several decades, research on post-traumatic complications has assumed a biphasic post-traumatic inflammation model. This model describes an initial proinflammatory systemic inflammatory response syndrome (SIRS), which was assumed to be mainly driven by the innate immune system, and a “counterbalancing” compensatory anti-inflammatory response syndrome (CARS) [
3,
5]. However, the theory of a simultaneous SIRS–CARS paradigm has been widened for further ongoing injury-caused inflammatory processes, as, for example, the organism’s effort to strike the delicate balance between a sufficient defense against putative pathogens entering through eventual wounds on the one hand, and reducing collateral damage by immune cells on the other hand [
7‐
9]. Furthermore, next to alterations of the innate immune system, the post-traumatic immunosuppression has been closely linked to modulations of the adaptive immune system, e.g., a shift from a T-helper cell type (Th)1- to a Th2-mediated immune response [
8‐
11]. Additionally, notably in the last two decades the biological host response to trauma, which initially has been characterized by massive cytokine release as well as the activation and recruitment of effector cells including antigen presenting cells, has further employed a large number of both microbial and host alarmins [
12‐
17]. Taken together, on a biochemical level, the post-traumatic immune response is not only activated by foreign non-self material, but includes endogenous factors as well, so-called danger-associated molecular pattern (DAMP), which are released from necrotic or physiologically “stressed” cells, and thus can initiate as well as recruit effector cells of the immune system [
18‐
20]. A large number of those endogenous nuclear or cytosolic triggers have been described to initiate and perpetuate the systemic post-traumatic and/or noninfectious inflammatory response; however, the knowledge on their precise role still remains unknown [
21‐
23]. In contrast, so-called pathogen-associated molecular patterns (PAMP) are compromised of the infectious and pathogen-induced highly conserved structures, such as CpG motifs [
24,
25]. The major DAMP, which are involved in endogenous signals originating from stressed, injured, or necrotic cells in the setting of trauma will be examined in this review.
Recognition, signaling and cellular response
The immune system, which has evolved over millions of years, can not only discriminate between self and non-self, but between safe and dangerous as well, as presented by Polly Matzinger in the “Danger Model”, expanding the work of Janeway and others [
18,
19,
24,
26,
27]. Thus, this complex response to stress employs numerous equivalent or comparable components of PAMP or DAMP, which can be found in most vertebrates, invertebrates and even plants [
24,
27].
As very potent triggers of inflammation, PAMP and/or DAMP are sensitized and recognized via pattern recognition receptors (PRR) [
28,
29]. Several classes of PRR have been identified so far, including the most prominent group of toll-like receptors (TLR), nucleotide oligomerization domain (NOD)-like receptors (NLR), members of the C-type lectin receptors (CLR) like mannose binding lectine (MBL) or receptor for advanced glycation end products (RAGE) among others [
28,
30‐
32].
In mammalian thirteen and in human ten different TLR types have been identified so far [
33‐
35]. Apart from their similar structures, they are either localized on the cell membrane (TLR1, 2, 4, 5 and 6), or on intracellular compartments, i.e., endosome membrane (TLR3, 7, 8 and 9) [
28,
31]. Membrane-bound TLR recognize microbial components and environmental danger signals, such as lipopolysaccharide (LPS) of Gram-negative, lipoteichoic acid (LTA) or peptidoglycan of Gram-positive bacteria, or even liporabinomannan (LAM) of mycoplasma and, e.g., endogenous high-mobility group box (HMGB) proteins or HEME, which are released from distressed cells, respectively [
28,
36‐
40]. Intracellular TLR recognize predominantly nucleic acids derived from bacteria and viruses, such as single or double-stranded RNA from viruses, unmethylated CpG motifs, or purine analogues as well as other components of cellular stress [
28].
Upon their activation, PRR transduce signals intracellularly, e.g., via mitogen-activated protein kinase (MAPK) signaling pathways to nuclei, where diverse transcription factors, among others the nuclear factor ‘kappa-light-chain-enhancer’ of activated B cells (NF-κB) become activated, subsequently inducing a cellular response [
41,
42]. Here, one prominent example constitutes the MyD88 pathway [
43]. TLR3 is the only TLR not using the MyD88-dependent pathway for signal transduction [
44]. The cellular response upon, e.g., NF-κB activation includes the expression of, e.g., cytokines or adhesion molecules to accelerate inflammation and diapedesis of the immune effector cells [
42]. In a feedback loop, those inflammatory mediators themselves can induce, e.g., DAMP to potentiate inflammation [
45].
NLR are sensitizing signals of cellular stress, such as adenosine triphosphate (ATP)-induced activation of P2X7 channels and the efflux of potassium ions, host cell-free nuclear deoxyribonucleic acid (DNA), reactive oxygen species (ROS) as well as bacterial peptidoglycans, crystalline material, peptide aggregates, bacterial toxins and many others [
46‐
48]. They are part of the multiprotein complexes, which mediate the cleavage of biologically inactive precursors of, e.g., IL-1β or IL-18 into their respective bioactive forms by the activated caspases 1 or 5, and which furthermore induce a specific form of cell death called pyroptosis [
47,
49‐
53]. Most described inflammasomes contain a NLR sensor molecule, such as NOD-, leucin-rich repeats (LRR)-, and pyrin domain-containing (NLRP), e.g., 1 or NLRP3 [
47,
52,
54,
55]. However, the direct link for the NLR-mediated inflammasome activation via binding of either PAMP or DAMP is still under discussion [
48,
53]. It is strongly discussed that the secretion of inflammasome-activated cytokines must be “prepared” by a priming stimulus, which is usually supposed to be mediated by a TLR, which in turn activates the NF-κB pathway, and the transcription of IL-precursors as well as inflammasome components [
56,
57]. In parallel, inflammasome induction by a DAMP as, e.g., potassium influx or binding of ATP to P2X7 is assumed to set off the NLR [
53,
56‐
61]. Furthermore, an activation via ROS has been discussed. The dsRNA-dependent protein kinase R (PKR) has been identified as a further player of the inflammasome pathway [
61‐
63]. Additionally, NLR with a N-terminal caspase activation and recruitment domain (CARD), which can bind RIP2, a protein kinase that can activate NF-κB and MAPK pathways inducing a response, are involved in signaling [
41].
Apart from the cleavage, and subsequent activation of certain cytokines, the inflammasome complex is capable of inducing cell lysis. In addition to necrosis and apoptosis, in 2001, the new concept of pyroptosis has been introduced [
64]. Pyroptosis is characterized by a well-orchestrated lysis of the cell, which is initiated by the inflammasome activation and consecutive formation of caspase-1-dependent pores of 1–2 nm width [
64]. In consequence, cells are prone to swelling and lysis, but also to the release of intracellular molecules, which act as DAMP, e.g., HMGB1 or ATP. Thus, pyroptosis represents an important mode of cell death in DAMP-mediated enhancing and spreading of the immune response, which not only mainly affects the cells of the myeloid lineage but also occurs in epithelial, endothelial cells and neurons.
C-type lectin receptors (CLR) bind mainly to PAMP, such as bacterial, fungal and viral carbohydrates in a calcium-dependent manner [
65]. There are two groups of transmembrane CLR, like dectin-1 or dectin-2 subgroups, and a group of soluble CLR including MBL, which comprise this large family of receptors that are expressed on most cell types including macrophages and dendritic cells (DC) [
65,
66]. The signaling pathways can either directly activate NF-κB, or affect signaling by TLR, triggering cellular phagocytosis, DC maturation, chemotaxis, respiratory burst, and cytokine production [
66]. In 2008, Yamasaki et al. found that macrophage-inducible C-type lectin (Mincle) senses nonhomeostatic cell death, and induces thereby the production of inflammatory cytokines and chemokines to potentiate the neutrophilic infiltration of damaged tissue [
67]. Hereby, a CLR activation due to a DAMP was introduced for the first time. The authors found that Mincle-expressing cells, mainly macrophages, were activated in the presence of necrotic dead of cells due to a component of small nuclear ribonucleoprotein, spliceosome-associated protein 130 (SAP130) [
67]. Recently, the endogenous Mincle ligand SAP130 was confirmed as a danger signal, which can be released by damaged cells, thereby activating inflammatory responses including inflammasome activation [
68].
The cell surface receptor for advanced glycation end products of proteins (RAGE), first described in 1992, belongs to the immunoglobulin superfamily. RAGE is a multiligand receptor that binds structurally diverse array of molecules, including DAMP-like HMGB1, but also S100 family members and amyloid-β proteins [
69‐
71]. RAGE is mainly expressed in the lung, which is intriguing its contribution to the response to environmental challenge/stress [
72]. Its activation plays a role in various diseases, including sepsis and cardiovascular disease among others [
73‐
75]. In general, RAGE is predominantly involved in the recognition of endogenous molecules released in the context of infection, chronic inflammation or physiological stress [
32]. It shares numerous TLR ligands and, therefore, RAGE–ligand interactions induce numerous cellular signaling pathways, which among others lead to the activation of different transcription factors such as NF-κB, activator protein (AP)-1, or signal transducers and activators of transcription (STAT-)3 [
32,
76‐
78]. The end products include proinflammatory mediators, such as tumor necrosis factor (TNF)α, generation of nitric oxide, several adhesion molecules and RAGE itself [
77,
79‐
82], which is in consequence upregulated at sites of ligand interaction, thereby causing a continuous inflammatory response [
77].
Conclusions
This review summarizes only a short list of currently discussed DAMP that play a role in the inflammatory or regenerative response upon trauma. The list is certainly both incomplete and provides only a limited overview to the concept of trauma-induced DAMP. Due to the bivalent character and often pleotropic effects of a DAMP, it is difficult to describe its “friend or foe” role in the post-traumatic inflammation and regeneration. It is indisputable that DAMP are obligatory for the immune response upon traumatic insult, both systemically as well locally in tissues. On the one hand, they can not only be used as biomarkers to indicate or monitor disease or injury severity, but also may be clinically applicable for better indication and timing of surgery. On the other hand, they constitute either negative or positive contributing factors for the disease development. However, due to the inflammatory processes at the local tissue level or the systemic level, their precise roles are not always clear to define. While in vitro and experimental studies allow for the detection of these biomarkers at the different levels of an organism—cellular, tissue, circulation—this is not always easily transferable to the human setting. Increased knowledge exploring this dual role of DAMP after trauma, and concentrating on their nuclear functions, transcriptional targets, release mechanisms, cellular sources, multiple functions, their interactions and potential therapeutic targeting is warranted. Adjacent to in vivo studies and, furthermore, based on sometimes contradictory findings, which originate from differences between the immune system of animals and human, as discussed in this article as well, clinical research is necessary.