Thermal injury is often associated with a proinflammatory state resulting in serious complications. After a burn, the innate immune system is activated with subsequent immune cell infiltration and cytokine production. Although the innate immune response is typically beneficial, an excessive activation leads to cytokine storms, multiple organ failure, and even death. This overwhelming immune response is regulated by damage-associated molecular patterns (DAMPs). DAMPs are endogenous molecules that are actively secreted by immune cells or passively released by dead or dying cells that can bind to pathogen recognition receptors in immune and nonimmune cells. Recent studies involving animal models along with human studies have drawn great attention to the possible pathological role of DAMPs as an immune consequence of thermal injury. In this review, we outline DAMPs and their function in thermal injury, shedding light on the mechanism of sterile inflammation during tissue injury and identifying new immune targets for treating thermal injury.

Damage-associated molecular patterns (DAMPs) are conserved molecular motifs that result from cell death or tissue injury (1, 2). They serve as important mediators linking sterile inflammation to end-organ damage and life-threatening disease through the modulation of the innate immune response. Many of these DAMPs are intracellular proteins (e.g., high-mobility group box 1 [HMGB1] and heat shock proteins) from different organelles that are released by dead or dying cells (3, 4), whereas others are nonprotein (e.g., ATP and DNA), extracellular matrix (ECM), or cell membrane components that may be upregulated and secreted after host recognition of tissue damage (5). Although thermal injury has complex pathological effects, it can produce significant destruction to s.c. layers, resulting in the activation of the innate immune system via the recognition of DAMPs by pathogen recognition receptors (PRRs). Consequently, the activation of DAMP pathways leads to cytokine production and overwhelming inflammation, which, in turn, exacerbates tissue damage and dysfunction (Fig. 1). The aim of this review will be to summarize the current knowledge of DAMPs and their immunopathologic roles in thermal injury.

FIGURE 1.

The immunopathogenic role of DAMPs in mediating thermal injury. DAMPs can be released by dead, dying, or injured cells during thermal injury. After release, DAMPs bind to PRRs expressed in immune (e.g., macrophages and neutrophils) and nonimmune cells (e.g., endothelial cells), leading to the activation of transcription factors, which ultimately results in excessive cytokine production and subsequent multiple organ failure.

FIGURE 1.

The immunopathogenic role of DAMPs in mediating thermal injury. DAMPs can be released by dead, dying, or injured cells during thermal injury. After release, DAMPs bind to PRRs expressed in immune (e.g., macrophages and neutrophils) and nonimmune cells (e.g., endothelial cells), leading to the activation of transcription factors, which ultimately results in excessive cytokine production and subsequent multiple organ failure.

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Although tissue damage following burn injury has been examined using validated experimental models, murine and rat models are the most widely used (612). The volume of injury is measured using the percentage of total body surface area (TBSA) of burn. Moreover, the severity of tissue injury is measured by the depth of burn involvement. First-degree burns are limited to the epidermal layer, with damage to epidermal keratinocytes and marked by erythema and pain. Second-degree burns are superficial or deep partial-thickness injuries that extend into the papillary dermis and reticular dermis, respectively. These burn injuries maintain the ability for epithelial regeneration and are marked by erythema, blisters, and severe pain. Third-degree burns extend into s.c. adipose with damage to dermal microvasculature, hair follicles, sebaceous glands, and sweat glands. These injuries are commonly associated with eschar formation, necrosis, and desensitization. Fourth degree burns extend into muscle and deeper layers associated with cellular necrosis and a layer of neutrophils demarcating viable from nonviable tissue. Commonly, these wounds are necrotic and insensate. Greater TBSA and severity portends worse outcomes and higher mortality (13, 14). The experimental models used to study burn injury use third-degree scald burn injury ranging in TBSA from 12.5 to 60% (15, 16). After thermal injury, inflammatory cells and innate immune markers are upregulated in various organs (7, 10, 12, 17). Multiple studies have shown that organs prone to increased inflammation include the heart, lungs, liver, intestines, and spleen (6, 7, 18, 19). The activated innate immune system can lead to altered metabolism, multiorgan failure, and death (20). The process by which these complications occurs is thought to be secondary to a DAMP-induced proliferation and activation of inflammatory cells via specific intra- and extracellular receptors (2123). These mechanisms will be discussed based on the subcellular location of DAMPs.

PRRs are the receptors used by both DAMPs and pathogen-associated molecular patterns (PAMPs). PAMPs are the components or products of microorganisms. These receptors activate downstream signaling after binding pathogen motifs (e.g., microbial nucleotides or proteins) or molecular patterns formed from cellular damage (e.g., host DNA, histones, and HMGB1). Known PRRs or sensors include TLRs, retinoic acid-inducible gene-I–like receptors, nucleotide-binding oligomerization domain-like receptors (NLRs), absent-in-melanoma 2–like receptors, C-type lectin receptors, advanced glycosylation end-product–specific receptors (AGER, also known as RAGE), cyclic GMP-AMP synthase (cGAS), and stimulator of IFN response cGAMP interactor 1 (STING1, also known as STING or TMEM173). Thermal injury may have similarities to other forms of tissue trauma (e.g., blunt, penetrating) and may share similar mechanisms of injury-related immune responses. For example, mitochondrial DAMPs have been correlated with neutrophil dysfunction in burns as well as blunt trauma, as studied in animals and humans (24, 25). However, the contrast between burn trauma and other tissue trauma has not been delineated in the literature, and this review will aim to expand on thermal injury. Although the above-mentioned immune modulators play a clear role in infection and sepsis, only a few of them have been evaluated during burn trauma. In particular, TLRs, NLRs, and AGER have become the main receptors responsible for DAMP-mediated inflammation during burns (2629). Moreover, several transcription factors, including NF-κB, AP-1, IFN regulatory factor 3 (IRF3), and IRF7, function as downstream NFs of DAMP activation to drive cytokine production and inflammatory cell infiltrate.

TLRs.

The TLR family consists of 13 members and is the most widely studied PRR in burns (23, 30, 31). The downstream adaptor proteins for TLRs include the MYD88 innate immune signal transduction adaptor (MYD88) or toll-like receptor adaptor molecule 1 (TICAM1, also known as TRIF) that ultimately aid in the signal transduction and activation of transcription factors to produce cytokines or other immune mediators (31). Of note, TLR2 and TLR4 have been widely investigated and shown to play an important role in initiating inflammation during burns (6, 811, 17, 19, 23, 27, 3243). Following burn injury, TLR2 is overexpressed on peripheral monocytes (27) and TLR4-deficient mice exhibit diminished inflammatory responses to thermal injury (9, 10, 3234, 39, 43). In addition to reducing inflammation, the absence of TLR4 may improve organ function (e.g., cardiac contractility and intestinal endothelial integrity) (6, 9, 32) and prevent tissue injury (e.g., lung edema) during burns in mice (34). The depletion of CD14 (the principal binding receptor for TLR4) in mice also has a role in reducing the production of circulating tissue necrosis factor (TNF), IL-1B, IL-6, and IL-10 with a concomitant preservation of cardiac function after burn injury (12). Moreover, the expression of CD86 (a costimulator protein responsible for the differentiation of plasma cells from B cells), IL-1B, and TNF are reduced in TLR2-deficient mice following burn injury (43). Notably, TLR1 may have a contradictory role in innate immune regulation as TLR1 gene expression is downregulated in human keratinocytes after severe burn injury (44). Furthermore, the TLR9 pathway is impaired in splenic dendritic cells of mice after burn injury, leading to dysfunction in a proinflammatory response as well as a blunted adaptive response (45). The other TLRs may play a role in innate immune signaling after burn injury, given an upregulation of their corresponding ligands. For example, profilin-1, a nuclear-derived DAMP, is upregulated after chronic endoplasmic reticulum (ER) stress, which likely occurs in thermal injury (28). Additionally, profilin-1 is known to bind to TLR11 and cause the activation of downstream events (46, 47). More studies are needed to confirm the activation of other TLRs in burn injury.

NLRs.

The NLRs are a group of cytosolic sensors that trigger innate immune signaling. There are 14 different members of the NLR subfamily known as NLRP, of which only two form a multicomplex inflammasome (NLRP1 and NLRP3) (48). NLRP3 is known for its canonical signaling after induction by multiple DAMPs or PAMPs to trigger inflammasome activation and IL-1 family release (48). Following thermal injury, NLRP3 is upregulated, leading to the cleavage of procaspase-1 into its active caspase-1 form, followed by cleavage of pro–IL-1B and pro–IL-18 into their active forms of IL-1B and IL-18, respectively (16, 4851). In addition to mice, the upregulation of NLRP3 has been observed at 12 h after burn injury in the rat lung, with corresponding increases in canonical cytokines (49). Furthermore, there is evidence that this NLRP3-dependent inflammasome is also activated in the heart and liver following thermal trauma (5052). NLRP3 knockout mice with 25% TBSA burns have altered liver metabolism and hepatic fatty deposition and increased browning of adipose tissue (52, 53). This has been translated into human studies with similar findings of changes in adipose tissue (50). Increased plasma levels of IL-1B as well as macrophage infiltrate in adipose tissue was observed in a study of 76 burn patients (50). The other pyrin domain inflammasome, NLRP1, has not been shown to be involved in burn-specific activation of inflammation. It also remains unclear whether NLRP3-mediated caspase-11 activation also contributes to an inflammatory response in burn injury.

AGER.

AGER is a member of the Ig superfamily (54) that presents in many different types of cells and tissues. Once a ligand binds to AGER, downstream signaling leads to the activation of NF-κB and subsequent cytokine production in various disease models (54). After thermal trauma, the expression of AGER is upregulated on splenic T cells (55). Importantly, the administration of anti-AGER Abs significantly increases the 7-d survival rate of 30% TBSA-induced burn injury in rats, which is associated with the upregulation of IL-2 and IL-12 (56). The relation between burn-induced AGER upregulation is likely through its well-studied DAMPs, such as HMGB1 and S100 proteins. This still needs to be elucidated given the paucity of studies investigating AGER and burn injury.

Other receptors.

Other receptors have been implicated in burn injury and inflammation. One such receptor is ST2, which, in its transmembrane form, will bind IL-33 to activate cytokine production via NF-κB signaling (57). Hacker et al. (58) conducted a prospective cohort study involving 32 burn patients with an average TBSA of 32.5% and analyzed serum concentrations of soluble ST2 and mortality. When compared with controls, patients with burn injury had higher levels of soluble ST2 that positively corresponded to higher mortality (57). Other receptors that likely play a role in the activation of the innate immune system but have yet to be fully elucidated include CD91, CD147, cGAS/STING1, IL-1R, leucine-rich α-2 gp1 (LRG), P2Y2, or P2 × 7. These receptors have known ligands that have been shown to be upregulated after burn injury, albeit to a lesser extent than some of the other well-known DAMPs (5963). The DAMPs for these receptors will be discussed separately.

The cellular location of DAMPs can be categorized based on their subcellular compartment and whether they are extracellularly active and degraded (64). Many DAMPs associated with thermal injury commonly originate in the nucleus, mitochondrion, storage granules, or the ER (Table I).

Table I.
DAMPs and their receptors in burn inflammation
LocationDAMPReceptor
Cytosol Cyclophilin A CD147 
 Uric acid NLRP3 
 S100A AGER, TLR4 
 Heat shock proteins TLR2 
 Ferritin TLR2, TLR4, AGER 
   
Mitochondria ATP P2Y2, P2 × 7, NLRP3 
 mtDNA TLR9, AGER 
 Cytochrome C LRG 
 mtROS 
   
Nucleus HMGB1 TLR2, TLR4, AGER, TIM3 
 Histones TLR2, TLR4, TLR9, AGER 
 IL-33 ST2 
 Profilin-1 TLR11 
   
Lysosome LL-37 (cathelicidin) P2 × 7, CXCR2, TLR3, TLR4 
   
ER Calreticulin CD91 
   
Plasma membrane Enolase-1 ApoB 
   
ECM Matrilin-2 TLR4 
 Fibrinogen GP2B 
 Hyaluronan NLRP3 
 Fibronectin TLR4 
 Enolase-1 ApoB 
LocationDAMPReceptor
Cytosol Cyclophilin A CD147 
 Uric acid NLRP3 
 S100A AGER, TLR4 
 Heat shock proteins TLR2 
 Ferritin TLR2, TLR4, AGER 
   
Mitochondria ATP P2Y2, P2 × 7, NLRP3 
 mtDNA TLR9, AGER 
 Cytochrome C LRG 
 mtROS 
   
Nucleus HMGB1 TLR2, TLR4, AGER, TIM3 
 Histones TLR2, TLR4, TLR9, AGER 
 IL-33 ST2 
 Profilin-1 TLR11 
   
Lysosome LL-37 (cathelicidin) P2 × 7, CXCR2, TLR3, TLR4 
   
ER Calreticulin CD91 
   
Plasma membrane Enolase-1 ApoB 
   
ECM Matrilin-2 TLR4 
 Fibrinogen GP2B 
 Hyaluronan NLRP3 
 Fibronectin TLR4 
 Enolase-1 ApoB 

ApoB, apolipoprotein B; GP2B, glycoprotein IIb/IIIa; mtROS, mitochondrial reactive oxygen species; NLRP, NOD-like receptor protein; ST2, IL 1 receptor; TIM, T cell Ig mucin.

Nuclear DAMPs.

Following thermal trauma, cellular death occurs via either regulated cell death or accidental cell death, resulting in the production of varying DAMPs. Nuclear DAMPs include nuclear-associated proteins as well as nucleic acids (27). One of the most widely studied is HMGB1 (27, 28, 65, 66), a nuclear protein that is secreted by immune cells to mediate proinflammatory responses (67). Specific to burn injury, there has been ample evidence in experimental models to support the role of HMGB1in a proinflammatory state (27, 28, 68, 69). For example, mice sustaining a 25% TBSA burn injury showed increased levels of plasma HMGB1 24 h later with corresponding increases in cytokines IL-6 and TNF (27). The mechanism of burn-induced cellular damage may be secondary to increased ER stress from an accumulation of misfolded proteins. HMGB1 and other DAMPs (histone H2A and profilin-1) can be released from hepatoma cells treated with a calcium pump inhibitor to mimic ER stress (28). Furthermore, the upregulation of HMGB1 has been established in burn patients. Burn wound edges and autologous donor skin were evaluated in nine burn patients with TBSA burns ranging from 2.4 to 35% and an overexpression of the HMGB1 protein was found compared with nonburned controls (70). The activity of HMGB1 is modulated by several different receptors, including TLR2, TLR4, AGER, and hepatitis A virus cellular receptor 2 (HAVCR2, also known as TIM3) (65, 66). Following burn trauma, HMGB1 may favor the TLR2 and TLR4 pathways rather than that of AGER (56, 71). The depletion of TLR4 may not impair HMGB1 translocation from nucleus to cytosol and its subsequent release in mice following 30% TBSA burn injury (34). Additionally, reduced acute lung injury in a TLR4 knockout model was noted as well as a reduction in lung neutrophil infiltrate (34). The mechanism by which inflammation is propagated may be secondary to the type of inflammatory cell involved. As the neutrophil plays an important role in acute lung injury, the monocyte may play a more important role in cytokine signaling and recruitment. Plasma levels of HMGB1 have the potential to act through the TLR2 receptor, likely on monocytes (27, 65). Indeed, unlike TLR4, TLR2 is upregulated on monocytes in animals after burn injury compared with nonburned animals (27). In addition to functioning alone, HMGB1 can be secreted as a complex with IL-1B to act on receptors of peripheral monocytes (71). Consequently, the downstream events for TLR activation, such as the phosphorylation of NF-κB, are blocked in burn injury after treatment with anti-TLR2 or anti-TLR4 Abs (72).

Another nuclear DAMP known to act via the TLR family is profilin-1 (46, 47). Profilin proteins play an important role in F-actin formation and in polymerizing actin (46). With tissue damage, profilin-1 may be released, causing an inflammatory phenotype via the TLR11 receptor mechanism (47). The role of profilin-1 after thermal injury is still unclear but thought to be a novel DAMP secondary to ER stress (27). DAMPs that use receptors other than the TLR family include ILs, specifically IL-33. IL-33 is a known proinflammatory DAMP associated with trauma (73). The free plasma IL-33 was highest at early time points after burn and continued to trend down thereafter in burn patients with an average TBSA of 32.5% (58).

Nuclear histones, especially histone 2A, are implicated in burn injury. An in vitro model using hepatoma cells showed increased levels of histone 2A and an associated increase in levels of IL-6 and TNF (28). These DAMPs are thought to activate the immune system via TLR2, TLR4, and possibly TLR9, although the exact mechanism in burn injury has yet to be elucidated (74).

Mitochondrial DAMPs.

The mitochondrion appears to have as many DAMPs associated with innate immune signaling as the nucleus (64). A well-known DAMP originating from the mitochondrion is mitochondrial DNA (mtDNA) (64). The DNA content of mitochondria is known to have evolved from a prokaryotic organism in a symbiotic manner, maintaining a CpG motif recognized by PRRs. After cellular stress or traumatic injury, mtDNA is released into the plasma where it has been shown to upregulate inflammation, most likely using TLR9 (64). The mechanism of mtDNA-induced inflammation following burn injury has not been fully explored and remains incomplete. Mice with 25% TBSA burns underwent bronchoalveolar lavage to obtain inflammatory cells, which showed an upregulation of TLR2 and TLR4, with no change in TLR9 receptors (15). Alternatively, mtDNA may cause inflammation independent of TLR9. The mtDNA is directly linked to an increase in plasma cytokine levels as well as neutrophil infiltrate within the lung (75). The transfusion of mtDNA isolated from burn-induced lung neutrophils to nonburned rats can cause lung edema and neutrophil infiltration (75). Moreover, splenic dendritic cells harvested from burned rats showed an increase in IL-10 after TLR9 activation without proinflammatory cytokines, strengthening the hypothesis that mtDNA-induced inflammation occurs via a non-TLR9 pathway (49). Human studies show plasma levels of mtDNA are increased after traumatic injury and are dose dependently correlated with mortality (76). There is a paucity of human burn studies involving mtDNA after injury and its correlation with inflammation and clinical outcomes.

Another mitochondrial DAMP well known in the animal model, but less studied in humans, is cytochrome C. Cytochrome C has been used as a proxy for evaluating mitochondrial damage (27). Thermally burned mice showed increased levels of cytochrome C after injury that correlated with increases in plasma cytokines such as IL-6, IL-10, and TNF (27). Inflammation associated with cytochrome C seems to be operating through the neutrophil (77, 78). After burn injury, neutrophils degranulate intracellular products leading to nearby tissue injury. This degranulation process is a normal function of innate immunity that mitigates the spread of infection. The neutrophil will undergo apoptosis, thereby ceasing the degranulation process to limit tissue damage. However, this process is altered during burn injury (77). Cytochrome C is released from mitochondria after thermal injury and binds to Apaf-1 to cause downstream cleavage of caspase-9 and caspase-3, leading to apoptosis. This delays apoptosis in neutrophils and prolongs the degranulation process, which contributes to inflammation-induced tissue injury (77). Although the receptor for cytochrome C has not been elucidated specifically in burns, LRG may be responsible for its activity (79).

Other mitochondrial DAMPs play a role in neutrophil-induced injury (27). ATP is thought to aid in neutrophil adhesion to endothelial cells by its interaction with the receptor P2 × 7, which is upregulated after burn injury (25, 29). The binding of ATP to P2 × 7 may trigger the NLRP3 inflammasome leading to IL-1B production and a proinflammatory response (80). Moreover, formyl peptides found within the mitochondrion are DAMPs that function as chemotactic proteins (81). Formyl peptides have not been implicated specifically after burn injury, but their roles after trauma have begun to be elucidated (81).

Storage granule DAMPs.

The neutrophil will undergo either a passive or active release of histones, DNA, and proteins that limit the spread of invading pathogens, and this process is termed NETosis. Several DAMPs have been implicated in NETosis, one of which is commonly found in storage granules such as lysosomes. Cathelicidin (LL-37) is an important protein known for its antimicrobial functions and is found in many different types of cells, including inflammatory cells such as monocytes and neutrophils (82). After cutaneous thermal injury, LL-37 has been shown to be upregulated in burned skin and concomitantly downregulated in unburned nearby skin (83). The mechanism of innate signaling of LL-37 has been well studied in nontrauma and nonburn models. LL-37 interacts with TLR3 and TLR4 to promote downstream inflammation and also interacts with other cell-specific receptors for pathogen clearance (84, 85). For example, neutrophils and monocytes can use the cell surface receptor CXRC2 to bind LL-37, leading to the endocytosis of invading pathogens (86). Moreover, LL-37 can bind to many different types of receptors depending on which cell is actively involved in pathogen clearance. The macrophage is thought to use the receptor P2 × 7 to bind LL-37 thereby guiding the internalization of pathogens (84).

ER DAMPs.

Calreticulin is an ER protein that functions to bind misfolded proteins to prevent erroneous exportation. Following 35% TBSA burn in a murine model, there is an increase in hepatic ER calreticulin 24 h after injury (87). The levels of hepatic calreticulin remain elevated after 21 d postburn, contributing to the depletion of ER calcium stores and subsequent ER stress (87). The ER stress seems to play a major role in the upregulation of the innate immune system and cytokine production during burn injury (52). IL-6 and IL-1B are upregulated following burn, which is related to NLRP3 activation and could potentially implicate calreticulin in the NOD-like receptor pathway.

Cytosolic DAMPs.

Ferritin is a cytosolic protein that functions to bind iron, which is toxic to cells in its unbound, free form. Ferritin has been shown to act as an inflammatory trigger, possibly using the TLR2, TLR4, and AGER receptors (23). Following burn injury, patients had a serial increase in serum ferritin as late as 14 d postburn (88). The authors of this study do not formulate a hypothesis as to which PRR is implicated, but based on nonburn studies, it is possible that the TLR or AGER receptors play a role. Furthermore, another group investigated the function of the S100A protein after burn injury and found that it interacted with TLR4 and AGER receptors, emphasizing the importance of these PRRs (89, 90). Despite this evidence, the burn trauma literature is lacking definitive pathways for many DAMP-induced inflammatory injuries.

Many of the major DAMPs associated with a proinflammatory state are intracellular, but there is continuing evidence that there are molecular patterns on the cell surface and in the ECM that can activate the innate immune system.

ECM DAMPs.

One of the more studied ECM DAMPs is hyaluronan, a glycosaminoglycan that contributes to synovial fluid lubrication and cell proliferation. After burn injury, an increase of plasma hyaluronan correlates with an increase in cytokines IL-6 and TNF (27). The mechanism for increased cytokine production may be through the NLRP3 inflammasome, given its necessity for the production of IL-1B in response to hyaluronan (91). The TLR family may also be implicated with hyaluronan given its association with IL-6 production (27). Furthermore, other DAMPs associated with increased inflammation in burns mechanistically use TLR2 and TLR4 (27, 40, 88). Plasma fibronectin peaked 3 h postburn injury compared with 24 h for hyaluronan (27). In addition, the PRR for the downstream production of cytokines may be TLR2 and possibly TLR4 on monocytes (27). Another ECM component includes the matrilin-2 protein, which is normally associated with von Willebrand factor. Serum matrilin-2 was observed in both a burn mouse model and in burn patients (40). Like the administration of TLR4-neutralizing Ab, thermal injury in a matrilin-2–deficient mouse showed a decreased production of cytokines IL-6, IL-1B, and TNF with a concurrent reduction of neutrophil infiltration in the lung (40). However, whether TLR4 is a direct receptor of matrilin-2 remains unknown.

Another less studied DAMP in burn injury is fibrinogen, which is a well-known glycoprotein complex that functions in coagulation after vascular injury. In a mouse model of third-degree burns, the plasma and muscle fibrinogen content was significantly upregulated with associated increases in TNF. The cytokine production is thought to occur through signaling via MCP 1 (MCP-1), although the receptor is still not fully understood (41). After vascular injury, fibrinogen is cleaved into its active fibrin form to aid in clot formation. The receptor for fibrinogen is G2PB under these physiological circumstances, although the proinflammatory cytokine mechanism still needs further elucidation.

Finally, there is one protein that appears to act as a DAMP from both the ECM as well as the plasma membrane. Enolase-1 is an enzyme involved in the glycolytic production of phosphoenolpyruvate (92). The protein is localized to the cytosol but has been shown to be secreted via exosomes in certain cell types. Intestinal epithelial cells cultured with IFNG are able to secrete exosomes with enolase-1 that may play a role in Ag presentation and a possible proinflammatory state (93). An in vitro model using hepatoma cells treated with an SERCA pump inhibitor (which causes ER stress) as well as enolase-1 results in an increase in IL-6 and TNF (28). The receptor responsible for this upregulation could be the NLRP3 inflammasome, although other nonburn studies show that ApoB can act as a receptor for enolase-1 (94). To date, there has been no research on the role of ApoB and burn injury.

The proinflammatory state following burn trauma is marked by an earlier and continual upregulation of plasma and tissue cytokines. There are many different cells that are involved in the production of these cytokines, including neutrophils, monocytes, lymphocytes, and tissue-specific macrophages (8, 27, 45, 95). The cytokines produced after thermal injury are best categorized by those that upregulate the inflammatory state and those that are known to downregulate inflammation (Table II).

Table II.
Cytokine production in burns
CytokinesFunctionReceptorsCellular OriginCellular Response
IL-1B Proinflammatory IL-1R1, IL-1R2 M, N 
IL-2 Proinflammatory IL-2RA, IL-2RB, IL-2RG T cell T cell 
IL-6 Proinflammatory IL-R6 
IL-12 Proinflammatory IL-12RB1 M, N T cell 
IL-18 Proinflammatory IL-18R 
IFNB Proinflammatory IFNAR1, IFNAR2 Fibroblast 
TNF Proinflammatory TNFRSF1A, TNFRSF1B M, N M, N 
IL-10 Anti-inflammatory IL-10RA, IL-10RB Monocyte, T cell 
IL-33 Anti-inflammatory ST2 
CytokinesFunctionReceptorsCellular OriginCellular Response
IL-1B Proinflammatory IL-1R1, IL-1R2 M, N 
IL-2 Proinflammatory IL-2RA, IL-2RB, IL-2RG T cell T cell 
IL-6 Proinflammatory IL-R6 
IL-12 Proinflammatory IL-12RB1 M, N T cell 
IL-18 Proinflammatory IL-18R 
IFNB Proinflammatory IFNAR1, IFNAR2 Fibroblast 
TNF Proinflammatory TNFRSF1A, TNFRSF1B M, N M, N 
IL-10 Anti-inflammatory IL-10RA, IL-10RB Monocyte, T cell 
IL-33 Anti-inflammatory ST2 

IFNAR, IFN-α/β receptor; M, macrophage; N, neutrophil; ST2, IL 1 receptor; TNFRSF, TNF receptor super family.

There have been many investigational studies exploring the clinical benefits of DAMP- and PRR-directed therapy following burn injury (Table III). The severity of burn injury could relate to the choice of therapy administered. For example, less severe burns may benefit solely from a topical emollient compared with a systemic administration. These therapies will be discussed in this review.

Table III.
Target therapeutics in burn inflammation
TherapyTarget ReceptorTarget DAMPTarget Cell TypeApplication
Cer. nitrate  HMGB1, hyal Topical 
Apyrase  ATP Topical 
Lappaconitine P2 × 7 ATP Systemic (injection) 
Glycyrrhizin TLR2, TLR4 HMGB1, fibrinogen Systemic (injection) 
Gelsolin  Cyt, HMGB1, S100 T Cell Systemic (injection) 
TXA  mtDNA Topical 
Cyclosporin A  mtDNA Systemic (injection) 
Baicalin  HMGB1 Systemic (injection) 
BAY11-7082 NLRP3  M, N Systemic (injection) 
Artemisinin NLRP3  In vitro 
Resolvin D2   In vitro 
17-B estradiol  Cyt, mtDNA Systemic (injection) 
miR-181c TLR4  Systemic (injection) 
Allopurinol  Uric acid Systemic (injection) 
TherapyTarget ReceptorTarget DAMPTarget Cell TypeApplication
Cer. nitrate  HMGB1, hyal Topical 
Apyrase  ATP Topical 
Lappaconitine P2 × 7 ATP Systemic (injection) 
Glycyrrhizin TLR2, TLR4 HMGB1, fibrinogen Systemic (injection) 
Gelsolin  Cyt, HMGB1, S100 T Cell Systemic (injection) 
TXA  mtDNA Topical 
Cyclosporin A  mtDNA Systemic (injection) 
Baicalin  HMGB1 Systemic (injection) 
BAY11-7082 NLRP3  M, N Systemic (injection) 
Artemisinin NLRP3  In vitro 
Resolvin D2   In vitro 
17-B estradiol  Cyt, mtDNA Systemic (injection) 
miR-181c TLR4  Systemic (injection) 
Allopurinol  Uric acid Systemic (injection) 

Cer. nitrate, cerium nitrate; Cyt, cytochrome C; hyal, hyaluronan; NLRP, NOD-like receptor protein; TXA, tranexamic acid.

PRR-directed therapies.

Experimental therapies involving the more common of the PRRs have been tested, mostly in an animal model. Given the well-known role of TLRs in inflammation-mediated injury after burn, it is not surprising that there have been studies investigating anti-TLR2 and -TLR4 activity. One of the more recent therapies tested was miR-181c (a microRNA [miR] that expresses human umbilical cord mesenchymal stem cell exosomes), which is known for its anti-TLR4 function. The miR is not fully understood, but is thought to play a role in apoptosis via posttranslational modification of certain proteins (42). The administration of human mesenchymal stem cell–derived miR to a burn rat model can cause a downregulation of TLR4 with concurrent reductions in TNF and IL-1B (42). Another more common therapy investigated in burn injury is that of glycyrrhizin. Glycyrrhizin is a saponin derived from the licorice root that has many anti-PRR (e.g., TLR2 and TLR4) and anti-DAMP (e.g., HMGB1 and fibrinogen) effects in burn models (41). Other PRRs have also been experimented with, which include the NLRP3 inflammasome as well as the P2 × 7 receptor for ATP. BAY11-7082, an NLRP3 inhibitor, reduces burn-induced inflammasome activation, cytokine production, and lung injury in a rat model (49, 96, 97). Additionally, the use of artemisinin, an antimalarial drug, following burn injury results in a reduction in neutrophil recruitment in heart and lung via the inhibition of the NLRP3 inflammasome (51). The P2 × 7 receptor that utilizes ATP has also been a target for therapy. Lappaconitine is a chemical that comes from the aconitum root that is known for its nonopioid analgesia (98). Burned rats treated with lappaconitine showed a reduction in both plasma TNF and IL-1B when compared with controls via desensitization of the P2 × 7 receptor (98). The reduction in IL-1B would also suggest a possible anti-ATP property in addition to targeting its receptor. The exact mechanisms of many of these therapies have yet to be fully expounded, emphasizing the importance of continued investigations.

DAMP-directed therapies.

DAMP-guided therapy appears to be more fruitful than PRR-directed therapy. As previously mentioned, ATP and its P2 × 7 receptor play an important role in a proinflammatory state and therapies have been directed at both proteins. Lappaconitine mechanism of action is thought to be desensitization of the P2 × 7 receptor, but its effect on the downregulation of IL-1B suggests a role in the NLRP3 inflammasome or a direct effect on ATP, signifying the importance of ATP as a target. One drug known for its ability to hydrolyze ATP is apyrase. Apyrase is an emollient that can reduce the amount of neutrophilic infiltration in burned skin as well as reduce the cytokines TNF and IFNB in burned mice (99). This type of therapy is easy to apply and has been used in burn patients with additional findings of antimicrobial activity thought to be via the inhibition of biofilm production (100).

Another DAMP that has produced several different therapies is mtDNA. A few therapies targeted at inhibiting or downregulating mtDNA include the use of cyclosporin A, tranexamic acid, and 17-B estradiol. Cyclosporin A is thought to block the mitochondrion permeability pore that leads to inhibition of mtDNA release into the cytosol (101). Treatment with cyclosporin A dose dependently attenuates mtDNA release and lung injury in burn models (101). Additionally, the reduction of cytochrome C was noted in lung tissue in mice treated with cyclosporin A, which suggests a possible antioxidant role of this therapy (101). Similarly, tranexamic acid, traditionally a procoagulant, also attenuates acute lung inflammation, shedding light on the importance of mitochondrial DAMPs in driving lung injury (102). Moreover, it appears that the downregulation of mitochondrial DAMPs, including mtDNA and cytochrome C, is also important in cardioprotection. The administration of 17-B estradiol to a burn rat model leads to a reduction in cytochrome C and mtDNA release from cardiomyocytes as well as improved cardiac function, partly through the downregulation of NF-κB–mediated cytokine production (26).

ATP has a clear detrimental role in cardiac function after burn, which is further elucidated with the discovery that vacuolar ATPase in cardiomyocytes is diminished after burn, resulting in cardiac dysfunction (75). The anti-inflammatory effect of therapies targeting ATP may benefit a variety of organ systems, rather than being tissue dependent. For example, another investigative therapy used for burns is gelsolin. Gelsolin is an extracellular protein that binds actin under normal physiology, but is reduced after thermal injury (103). Gelsolin leads to a reduction in brain inflammatory infiltrate in addition to reduced apoptosis with findings of lower IL-1B, IL-6, and HMGB1 (69). Another group of researchers discovered decreased pulmonary microvascular permeability with gelsolin infusion following burns, possibly via the targeting of HMGB1 or other known DAMPs, emphasizing the utility of this treatment (103).

Targeting HMGB1 may be a high-yield endeavor, given the success of glycyrrhizin and other similar therapies. Cerium nitrate has been tested on burn eschar in a rat model, with findings consistent with an anti-inflammatory response with decreased HMGB1 release (104). However, cerium nitrate fails to limit neutrophil infiltration and the release of other DAMPs, such as cytochrome C and fibronectin (104). The utility of DAMP-directed therapies may depend on eschar penetration. Another HMGB1-reducing agent is baicalin, a known anxiolytic derived from Scutellaria leaves (105). The administration of baicalin to burned rats via i.p. injection causes a reduction in HMGB1 and myeloperoxidase in lung tissue, which contributes to limiting acute lung injury (106). The mechanism of action of baicalin may be an NLRP3 inhibitor as well as the upregulating of superoxide dismutase, which adds to the complexity of its full range of actions and effects.

Oxidative stress as a mechanism of tissue injury after burn injury has been established, specifically in cardiac tissues (26, 69). Early investigations of superoxide dismutase, xanthine oxidase, and the use of allopurinol showed cardiovascular benefits. Plasma uric acid levels are known to increase with the severity of burns, providing a conceptual mechanism for allopurinol (107). For example, burned rats treated with allopurinol showed a reduction in cardiovascular resistance as well as attenuated cardiac contractile dysfunction, effects that were similar in rats undergoing neutrophil depletion, thereby underscoring the important relationship between oxidative stress and the inflammatory response (108, 109). Although the list of therapies presented in this review is not exhaustive, the described investigative agents have proposed mechanisms of action that coincide with known receptors and DAMPs involved in inflammation-mediated injury after thermal trauma. Ongoing therapeutic investigations are needed to fully encompass the complex network of interactions responsible for inflammatory damage.

Thermal injury leads to a significant release of DAMPs from multiple sources that function to shape a sterile inflammatory response. This response is paramount for end-organ damage and poor clinical outcomes. The excessive activation of DAMP pathways plays a vital role in triggering the systemic inflammation seen after severe burns, acting via specific cytokine signals. These pathways have led to a plethora of investigative therapies that counteract the burdening inflammation seen with burn injury. Although much progress has been made, investigative drug trials as well as ongoing basic research are needed to treat and prevent the damage mediated by the inflammation following burn injury. In addition, a better understanding of the different types of cell death and the network of DAMPs released and their immune activity will undoubtedly have the potential to improve the diagnosis and treatment of sepsis and burn patients (110, 111).

We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for critical reading of the manuscript.

Abbreviations used in this article:

AGER

advanced glycosylation end-product–specific receptor

DAMP

damage-associated molecular pattern

ECM

extracellular matrix

ER

endoplasmic reticulum

HMGB1

high-mobility group box 1

LRG

leucine-rich α-2 gp1

miRNA

microRNA

mtDNA

mitochondrial DNA

NLR

nucleotide-binding oligomerization domain-like receptor

PAMP

pathogen-associated molecular pattern

PRR

pathogen recognition receptor

TBSA

total body surface area.

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The authors have no financial conflicts of interest.