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Originally published online as doi:10.1189/jlb.0503233 on October 13, 2003

Published online before print October 13, 2003
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(Journal of Leukocyte Biology. 2004;75:400-407.)
© 2004 by Society for Leukocyte Biology

Injury, sepsis, and the regulation of Toll-like receptor responses

Thomas J. Murphy, Hugh M. Paterson, John A. Mannick and James A. Lederer1

Department of Surgery, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts

1 Correspondence: Department of Surgery (Immunology), Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: jlederer{at}rics.bwh.harvard.edu


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ABSTRACT
 
Although we tend to think that the immune system has evolved to protect the host from invading pathogens and to discriminate between self and nonself, there must also be an element of the immune system that has evolved to control the response to tissue injury. Moreover, these potential immune-regulatory pathways controlling the injury response have likely coevolved in concert with self and nonself discriminatory immune-regulatory networks with a similar level of complexity. From a clinical perspective, severe injury upsets normal immune function and can predispose the injured patient to developing life-threatening infectious complications. This remains a significant health care problem that has driven decades of basic and clinical research aimed at defining the functional effects of injury on the immune system. This review and update on our ongoing research efforts addressing the immunological response to injury will highlight some of the most recent advances in our understanding of the impact that severe injury has on the innate and adaptive immune system focusing on phenotypic changes in innate immune cell responses to Toll-like receptor stimulation.

Key Words: innate-immune system • adaptive-immune system • inflammation • SIRS • CARS • cytokines


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FUNCTIONAL EFFECTS OF SEVERE INJURY ON THE IMMUNE SYSTEM
 
Like most physiological responses, the injury response is a dynamic process that follows a general pattern that has been defined based on clinical and scientific observations. As illustrated in Figure 1 , the early response to injury has been defined clinically as the systemic inflammatory response syndrome (SIRS), and as its name implies, this is the proinflammatory phase of the host response to injury. SIRS is an inflammatory immune response and as such, is mediated primarily by cells of the innate immune system. One current problem with the clinical definition of SIRS is that it attempts to define a broad spectrum of complex host responses to injury and sepsis. For this reason, a small group of investigators representing a number of scientific and clinical societies have made a recent attempt to better define SIRS in an attempt to more accurately diagnose the host response to injury and sepsis [1 ]. In some patients, a counterinflammatory response can develop after the initial SIRS response, CARS [2 ]. The CARS response has been classified as a compensatory, anti-inflammatory response, as it is often associated with the development of immune suppression and the overproduction of anti-inflammatory cytokines by T cells [3 , 4 ]. An additional component of the injury response referred to as secondary SIRS can develop if opportunistic infections set in [5 ]. This secondary inflammatory response occurring after the initial resuscitation period has also been referred to as the two-hit response model or hypothesis [5 , 6 ]. This review presents the position that the two-hit response or secondary SIRS may be driven primarily by the host response to the infection, and if this response is excessive, this in turn might lead to the development of MODS and death in some patients.



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  		Figure 1. Model depicting the immunologic and clinical consequences of severe injury. This diagram illustrates the inter-relationship between changes in host immune-response phenotype and clinical symptoms/outcomes following major injury. Early after injury, the SIRS often develops, putting the injured host at risk of developing multiple organ dysfunction syndrome (MODS) and death if the systemic injury response is excessive. The SIRS response is the proinflammatory arm of the injury response. In those patients surviving this initial injury-response phase, the compensatory anti-inflammatory response syndrome (CARS) may occur. In addition to being counterinflammatory, the CARS response is associated with the development of post-injury-immune suppression and thus, places the injured host at risk of developing nosocomial or opportunistic infections. Given the inflammatory nature of the innate-immune response at this time point post-injury, the injured host may be at increased risk of developing a severe secondary SIRS response and MODS. Although an oversimplified view of this complex, host-immune response, this diagram illustrates the wide deviation between innate- and adaptive-immune phenotypes, which occurs following severe injury.

These defined, injury-induced changes have also been shown to correlate with changes in innate and adaptive immune functions [2 , 4 ]. Although oversimplified, we have attempted to illustrate in Figure 1 some of the broad conclusions that can be made regarding the influence of severe injury on host immunity. First, the innate immune system appears to display a gradual increase toward heightened inflammatory reactivity, and the adaptive immune phenotype shifts toward a more counterinflammatory phenotype [7 ]. Overlaying these general, injury-induced, phenotypic changes onto what has been described to occur in critically injured patients illustrates that injury leads to a wide imbalance in immune function (Fig. 1) . This in turn disrupts immune homeostasis and thus predisposes the injured host to developing immune suppression, opportunistic infections, sepsis, and potentially adverse, exaggerated inflammatory responses against sepsis-causing bacteria or their toxic products.


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INJURY EFFECTS ON INNATE IMMUNE RESPONSES
 
It has been suggested that injury triggers a cascade of systemic, proinflammatory reactions based mostly on observations leading to the clinical definition of SIRS. This has led to the simplistic idea that injury induces a "cytokine storm", which then sets in motion the downstream, phenotypic changes in immunity [8 , 9 ]. But, the reality is that the innate host inflammatory response to injury has not been as well defined, as is the case for the other systemic inflammatory responses such as the host response to bacterial endotoxin or lipopolysaccharide (LPS) challenge. A number of studies have documented that various types of experimentally induced tissue injury do indeed cause an increase in circulating inflammatory cytokines [10 11 12 ]. Those cytokines shown to be elevated in the circulation of patients at early time points (within 1 day after major injury or surgery) include interleukin (IL)-1, IL-6, IL-10, and tumor necrosis factor (TNF) [13 14 15 16 ]. Similar patterns of cytokine induction have been observed in several different animal-injury models [9 , 17 , 18 ]. It is important to note that many of these studies did not determine the cellular sources of these cytokines. However, the rapid appearance of these factors in the circulation would suggest that innate-immune cell types, such as tissue macrophages, dendritic cells (DCs), or neutrophils infiltrating the injury site, are likely sources. Circulating levels of several acute-phase proteins, including C-reactive protein [19 ], serum amyloid A [20 ], procalcitonin [21 ], C3 complement [22 ], and haptoglobin [22 ], have also been shown to increase after injury, providing further evidence that injury causes a systemic host response.

A recent study demonstrating that necrotic tissue can induce cytokine expression from macrophages supports the exciting idea that tissue damage may directly trigger innate-inflammatory reactions [23 ]. Other endogenous mediators related to the injury response that might play a role in stimulating the release of inflammatory cytokines following injury include several heat shock proteins (HSP60, HSP70, GP96), components of the clotting cascade (fibronectin A, fibrinogen), chromatin-immunoglobulin G (IgG) complexes, and high-mobility group B1 protein [24 ]. It is our opinion that the discovery of these endogenous factors capable of inducing inflammatory responses through interaction with Toll-like receptors (TLRs) or other as-yet unidentified innate immune receptors is a major advance in linking injury responses to the initiation of specific changes in innate and adaptive immune function. In addition to being possible inducers of the injury response, they may also play a central role in regulating the innate and adaptive immune response to severe injury.


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INJURY EFFECTS ON THE ADAPTIVE IMMUNE SYSTEM
 
Early work addressing how injury influences the adaptive immune response used delayed-type hypersensitivity (DTH) responses as an approach to judge the effects of injury on the immune system. The results of these studies demonstrated that severely injured individuals or patients who underwent major surgery displayed a transient loss of skin DTH reactivity against recall antigens [25 , 26 ]. In addition, some of these reports showed that the reduced DTH response occurred in parallel with a significant reduction in mitogen-stimulated proliferation by peripheral blood mononuclear cells [27 28 29 ]. Subsequently, it was demonstrated that the reduced proliferation correlated with a reduction in mitogen-induced IL-2 production, suggesting that injury had an effect on T cell responses [30 , 31 ]. In more recent years, several research groups have documented that the injury-induced change in mitogen-stimulated responses was also associated with increased production of counterinflammatory-type cytokines such as IL-4 and IL-10, along with a reduction in interferon-{gamma} (IFN-{gamma}) production [32 33 34 ]. It is interesting that it was shown that severely injured patients developed a relative increase in serum IgE levels, an antibody isotype indicative of strong T helper cell type 2 (Th2) responses [35 ]. Taken together, these clinical observations formed the basis for the hypothesis that injury might induce a phenotypic switch in the adaptive-immune response toward increased Th2 responses. Further studies using several different mouse-injury models confirmed that severe injury causes a phenotypic switch in T cell cytokine production characterized as an increase in mitogen or anti-CD3 antibody-stimulated Th2 cytokine production (IL-4 and IL-10) along with suppressed Th1 (IL-2 and IFN-{gamma}) cytokine production [36 37 38 39 ]. The increased expression of a Th2 phenotype does not occur immediately after injury but is most evident approximately 1 week after the injury. This general observation suggests that although the effects of injury on the adaptive-immune system are initiated at the time of injury, the phenotypic shift is displayed in a delayed manner, suggesting it is a developed immune response. Because of the mutually antagonistic character of Th1 and Th2 responses, the injury-induced skewing of the immune system toward a Th2 phenotype appears to be associated with a loss of Th1 function. The results of immunization studies performed in mice demonstrated that severe injury does indeed suppress Th1 responses in vivo as determined by a loss of Th1 antibody-isotype formation [40 ]. Thus, our current understanding of how injury influences the adaptive-immune system supports the hypothesis that the immune suppression that develops following severe injury involves a suppression in Th1-immune function, occurring along with a relative skewing in the adaptive immune system toward an enhanced Th2 phenotype.


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REGULATORY INTERACTIONS BETWEEN THE INNATE AND ADAPTIVE IMMUNE SYSTEMS FOLLOWING INJURY
 
One potential explanation for the skewing of the adaptive immune system toward an anti-inflammatory, Th2 phenotype following injury is that it is a protective immune response that serves to mollify injury-induced inflammation. To directly address this question, we turned to using recombinase-activating gene 1 (Rag1)-deficient (Rag1-/-) mice, which lack an adaptive immune system for our injury studies, reasoning that this approach would allow us to determine if the adaptive immune system plays a part in regulating changes in the innate immune system following severe tissue injury [41 ]. We initially tested whether spleen cells from sham versus burn-injured C57BL/6 Rag1-/- mice and C57BL/6 mice differ in their response to LPS at 7 days. To compare as equivocal populations of spleen cells as possible, spleen cells from the C57BL/6 mice were first depleted of T and B cells using magnetic beads before being stimulated with LPS in vitro. The results of these studies revealed that spleen cells from burn-injured Rag1-/- mice displayed significantly higher LPS-induced TNF-{alpha} and IL-6 production than spleen cells from burn-injured C57BL/6 mice, suggesting that injury in the absence of adaptive immune regulation leads to a more heightened inflammatory phenotype [42 ]. We then demonstrated that the adoptive transfer of T and B cells into Rag1-/- mice prevented the heightened LPS response displayed by Rag1-/- mice, providing more evidence to suggest that the adaptive immune system plays an active role in controlling the innate immune response to injury [42 ]. Continued investigations using CD4-/- and CD8-/- mice as an approach to determine which major T cell subset might be responsible for this regulation point toward CD4+ T cells as playing a dominant role in regulating the innate-inflammatory response to injury (Murphy et al., manuscript in preparation). Several recent reports examining a mouse colitis model have also shown that CD4+ T cells can control the excessive inflammatory response in their mouse model [43 , 44 ]. This same group has recently reported that the CD25+-expressing CD4+ T cell subset, referred to as regulatory CD4+ T cells, is mediating the counterinflammatory response in the mouse colitis model [45 ]. Thus, based on the results of our recent work and these above-mentioned mouse colitis studies, we believe the adaptive immune system might play a more active role in controlling the innate-inflammatory-immune response to injury than previously realized.


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TLR RESPONSES AFTER INJURY AND SEPSIS
 
The dissection of how cells signal responses to a wide range of microbial antigens exploded with the discovery that the lps mutation responsible for the LPS-hyporesponsive nature of C3H/HeJ and C57BL/10ScNcr mice was mapped to mutations in a gene with high homology to a Drosophila melanogaster gene, Toll [46 ]. In Drosophila, this gene was identified as playing a significant role in embryogenesis, but it was also involved in Drosophila immunity, as Toll mutant flies displayed poor resistance to microbial infections [47 ]. Further studies using TLR4 gene-transfected cell lines verified that the lps gene was indeed TLR4, a signaling receptor for LPS [48 ]. This discovery brought about a rapid identification of a family of mammalian TLR genes, which now include 10 human and nine murine TLR genes [49 ]. The number of microbial products that are recognized by TLRs is expanding, which suits their original definition as pattern recognition receptors, recognizing pathogen-associated molecular patterns [50 ]. However, the discovery that TLRs also have the capacity to recognize endogenous or self-antigens suggests that their function may not be restricted to the recognition of pathogens. The TLR family and the microbial-versus-endogenous host-derived factors they recognize are listed for comparison in Table 1 .


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  		Table 1. Microbial Versus Endogenous TLR Ligands

As TLRs function to initiate innate immune reactivity against a wide variety of pathogens, it is not surprising that they use shared signaling pathways [74 , 75 ]. Once triggered, TLRs induce inflammatory cytokines using the signaling-adaptor molecules, myeloid differentiation factor 88 (MyD88) or Toll-IL-1-resistance adaptor-like protein (TIRAP). Signaling then proceeds toward nuclear factor-{kappa}B activation through a series of signaling intermediates including several different IL-1 receptor-associated kinase isoforms that have recently been shown to have positive and negative regulatory effects on TLR signaling [76 ]. Although TLRs use shared signaling intermediates, mounting evidence suggests TLRs have the capacity to stimulate differing functional responses. For instance, activating macrophages through the TLR4 pathway leads to higher induction of IL-1ß, IL-12, IFN-{gamma}, and nitric oxide than if these same cells are activated using TLR2-specific ligands [77 ]. Furthermore, the existence of MyD88-dependent and MyD88-independent TLR signaling pathways and the discovery of other signaling-adaptor molecules, such as TIRAP, provide further evidence supporting the idea that TLR signaling can trigger a more complex array of responses than originally predicted [78 , 79 ].

Our interest in the link between the injury response and TLR biology stems from the general and well-established observations that macrophages and neutrophils display a hyperinflammatory phenotype following severe injury [80 81 82 ]. Moreover, the evolutionarily conserved nature of the TLR genes and the assumption that the injury response is a primitive, immune response, in addition to the realization that stress-response mediators or tissue damage can stimulate endogenous TLR responses, suggested to us that TLRs may regulate or be modulated by injury.

Initial studies specifically addressing the impact of injury on TLR responses compared LPS, lipid A, or Staphylococcus aureus peptidoglycan stimulation of spleen cells harvested from sham versus burn-injured mice at 3 h, 1 day, or 7 days after injury to determine how injury influences early-versus-late TLR4 and TLR2 responses [83 ]. In that study, we used IL-1ß, IL-6, and TNF-{alpha} production to judge the influence of injury on TLR responses. Our original hypothesis with regards to the early injury response was that TLR4 and TLR2 responses should be suppressed early after injury in a manner analogous to the well-described tolerance or cross-tolerance response that occurs following activation of TLR signaling. In those studies, it was shown that prior exposure of TLR-reactive cells to TLR stimulation led to a markedly suppressed signaling response to TLR restimulation with the "tolerizing" TLR agonist or even an agonist for another TLR [84 85 86 ]. To our surprise, we did not observe a significant increase or decrease in TLR4- or TLR2-stimulated IL-1ß, IL-6, and TNF-{alpha} production at 3 h after injury, and we observed enhanced TLR responses by 1 day after injury. These findings suggested to us that injury itself did not cause hyporesponsive TLR signaling through a mechanism similar to what has been observed for TLR-initiated, inflammatory responses. Instead, injury sets in motion an increase in TLR responses that is detectable within 1 day after injury and becomes even more pronounced by 7 days after injury. Subsequent experiments using intracytoplasmic cytokine staining identified macrophages and DCs as the cells responsible for the enhanced TLR4- and TLR2-stimulated cytokine production.

We believe that enhanced TLR responses might be a unique feature of the host response to injury and may also contribute to the development of secondary SIRS if infectious complications arise in severely injured patients. In support of this idea, the results of studies addressing the pathophysiological consequences of increased TLR4 responses following burn injury in mice have revealed that injured mice develop enhanced susceptibility to LPS-induced lethal shock at 7 days after burn injury (Murphy et al., manuscript in preparation). Moreover, polymicrobial infection in mice induced by cecum ligation and puncture (CLP) during this same time period after burn injury consistently demonstrates a marked difference in the survival of sham versus burn-injured mice [87 , 88 ]. This suggests that the combination of suppressed adaptive immune function and enhanced host responsiveness to sepsis-causing bacteria might be central to the development of MODS in critically injured patients.


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DIFFERENTIAL INFLUENCE OF INJURY AND SEPSIS ON TLR RESPONSES
 
A limited number of studies have addressed the influence of injury on cell-surface TLR expression and responses, and relatively more is understood about how TLR agonists and sepsis influence TLR reactivity. The findings from our studies using the mouse thermal injury model suggest that injury augments TLR responses without significantly changing cell-surface TLR2 or TLR4 expression [83 ]. Several other reports have also documented that burn injury or hemorrhage can lead to an increase in LPS-mediated responses by splenic macrophages or liver Kupffer cells [81 , 89 90 91 ]. Another report showed that hemorrhagic shock blocked the ability of LPS to tolerize the lung against a secondary LPS challenge and that the injury effect was independent of changes in TLR4 gene expression [92 ]. These observations are in direct contrast to data demonstrating that TLR4 or TLR2 stimulation can significantly modulate the expression and response of these TLRs [85 , 93 94 95 ].

This dichotomy in the regulation of TLR responses between injury and sepsis prompted us to directly compare the effects of injury versus sepsis on TLR4 responses and cell-surface expression. We observed that mice given a nonlethal septic challenge by the CLP method had a slight increase in cell-surface TLR4–MD-2 expression on splenic macrophages at 7 days after sepsis, and burn injury did not cause any marked change in macrophage TLR4–MD-2 expression as judged by fluorescein-activated cell sorter (FACS; Fig. 2 ). We next compared the effects of injury versus sepsis on LPS-induced TNF-{alpha} expression in these same macrophage populations to determine how these differing insults affect TLR4-mediated responses. As shown in Figure 3 , we observed a marked increase in LPS-induced TNF-{alpha} expression by splenic macrophages prepared from burn-injured mice, whereas TNF-{alpha} expression levels did not increase or decrease in macrophages prepared from CLP-challenged mice. The findings from this simple comparative study highlight major differences between how injury and sepsis regulate cell-surface TLR4 expression and responses. Although we demonstrate increased TLR4–MD-2 expression on macrophages from mice given a septic challenge, this did not lead to increased LPS-induced cytokine expression. In contrast, burn injury significantly increased LPS-induced cytokine expression by splenic macrophages without significantly modulating cell-surface TLR4–MD-2 expression levels. Therefore, injury and sepsis demonstrate divergent effects on TLR4 responses. Perhaps, the augmented TLR4 response seen after injury evolved as a protective mechanism to enhance innate-immune function and help the injured host-control infections, whereas the lack of increased TLR4 responses following a significant sepsis event may serve to neutralize potential, ongoing, TLR4-driven responses.



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  		Figure 2. Cell-surface TLR4–MD-2 staining on macrophages from burn-injured versus CLP-challenged mice. Groups of male, C57BL/6 mice underwent sham or burn injury while under anesthesia. Additional groups of male, C57BL/6 mice underwent sham surgery or the CLP technique to initiate polymicrobial sepsis [87 ]. Seven days later, spleen cells were prepared and then surface-stained with fluorescein isothiocyanate (FITC)-labeled anti-F4/80 antibody and phycoerythrin (PE)-labeled anti-TLR4–MD-2 antibody. Control stains were performed using a PE-labeled antibody of the same isotype as the TLR4–MD-2 antibody. The histograms shown represent the relative levels of PE staining on gated F4/80+-staining cells; n = 6–8 mice per group.



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  		Figure 3. Comparative LPS-induced TNF-{alpha} expression by splenic macrophages from burn-injured versus CLP-challenged mice. Groups of male, C57BL/6 mice underwent sham injury, burn injury, sham surgery, or the CLP technique while under anesthesia. Seven days later, spleen cells were prepared and then stimulated ex vivo with 1 µg/ml LPS (highly purified 011:B4) for 6 h in the presence of 10 µg/ml brefeldin A to prevent cytokine secretion. Cells were then stained with FITC-labeled anti-F4/80 antibody. Following fixation with a 0.1% paraformaldehyde solution, the cells were permeabilized using 0.25% saponin and then stained with PE-labeled anti-TNF-{alpha} antibody or isotype-control IgG antibody. The stained cells were analyzed by flow cytometry to determine the percentage of TNF-{alpha}-expressing F4/80+ cells shown in the upper-right quadrants of these FACS plots. The FACS dot-plots shown represent the relative levels of PE staining on gated F4/80+-staining cells; n = 6–8 mice per group.


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FUTURE CHALLENGES
 
Although there have been recent advancements in our understanding of how severe injury influences the immune system, we are far from understanding the inter-relationship between changes in immune function and predisposition to opportunistic infections following severe injury. The current model displayed in Figure 1 serves to illustrate that injury causes a wide imbalance in host immune function. As such, the combination of suppressed, adaptive immune function and augmented, innate immune reactivity directed against invading pathogens might set in motion a critical situation that can lead to lethal consequences. Future studies addressing the effects of injury on the innate immune system will need to clarify the signals that trigger enhanced TLR4 and TLR2 responses. These may include necrotic tissue or stress factors including ancient innate immune mediators such as complement or other acute-phase reactants. Also, a link between the enhanced TLR responses following severe injury and suppressed immunity against pathogens will need to be established to determine if the severely injured host dies of infection, the response to infection, or a combination of both. In closing, the idea that "danger" can play a significant role in initiating an immune response is not a difficult concept to embrace, but an understanding of how tissue injury might regulate the immune response will require a significant amount of focused research effort to address this complex issue [96 ].


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ACKNOWLEDGEMENTS
 
This research work was supported by grants from the National Institutes of Health (GM57664 and GM35633), the Brook Fund, and the Julian and Eunice Cohen Fund for Surgical Research.

Received May 20, 2003; revised September 24, 2003; accepted September 25, 2003.


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Z. H. Nemeth, B. Csoka, J. Wilmanski, D. Xu, Q. Lu, C. Ledent, E. A. Deitch, P. Pacher, Z. Spolarics, and G. Hasko
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K. Vakharia and J. P. Hinson
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