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Originally published online as doi:10.1189/jlb.1206752 on May 10, 2007

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(Journal of Leukocyte Biology. 2007;82:282-285.)
© 2007 by Society for Leukocyte Biology

Pivotal Advance: Endogenous pathway to SIRS, sepsis, and related conditions

Amy H. Tang*,{dagger},{ddagger}, Gregory J. Brunn*,§, Marilia Cascalho*,{dagger},||,¶ and Jeffrey L. Platt*,{dagger},||,¶,1

* Transplantation Biology Program and the Departments of
{dagger} Surgery,
{ddagger} Biochemistry and Molecular Biology,
§ Pharmacology,
|| Immunology, and
Pediatrics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

1 Correspondence: Transplantation Biology, Mayo Clinic, 200 First Street, S.W., Medical Sciences 2-66, Rochester, MN 55905, USA. E-mail: platt.jeffrey{at}mayo.edu

ABSTRACT

TLRs are usually thought to recognize substances produced by microorganisms and thus, to initiate host defenses. This concept, however, fails to explain some functions of this family of receptors. Recognition of endogenous substances may explain the broader functions of TLRs in physiology and disease. Activation of TLRs by endogenous substances necessitates vigorous control of the function of the receptors. This communication will summarize a line of research, which points to an endogenous agonist for TLR4 and a putative mechanism for controlling the function of that receptor.

Key Words: Toll-like receptors • systemic inflammatory response syndrome • heparan sulfate

How the immune system recognizes and neutralizes the vast diversity of microorganisms and toxic substances, which might cause harm, has been considered a question of the greatest importance for more than a century [1 ]. For the adaptive immune system, this question is addressed by the vast repertoires of B lymphocytes and T lymphocytes, which can recognize billions of different structures, and owing to deletion of self-reactive lymphocytes, potentially distinguishes what is foreign from what is self. To achieve vast diversity, the size of each clone population must be small, and hence, immunological memory is needed to generate enough reactive lymphocytes to mount protective responses. Despite the specificity, immune regulation mounted over a period of weeks is needed to prevent those responses from damaging, autologous tissues. The challenge for the innate immune system is far greater. To avoid overwhelming sepsis, the innate immune system must recognize and control microorganisms as diverse as those recognized by adaptive immunity, and it must be controlled immediately. The responses of the innate immune system must also minimize inadvertent damage to tissues instantaneously.

The challenge of recognizing diverse, extracellular microorganisms in the innate immune system is thought to be met, at least in part, through the function of TLRs, which are best known for recognizing pathogen-associated molecular patterns (PAMPs) [2 3 4 ]. As one example, TLR4 recognizes LPS, an abundant component of the cell wall of gram-negative bacteria [5 ]. TLR1, TLR2, and TLR6 recognize peptidoglycan, a component of the cell wall of gram-positive bacteria, and zymosan, a component of yeast [6 ]. TLR9 responds to CpG DNA motifs common to bacteria. TLR3, TLR7, and TLR8 respond to RNA structures common to viruses [6 ].

Although the recognition of PAMP by TLR may explain the recruitment of innate immunity in some cases, the interaction fails to explain fully how TLR can detect all microorganisms, especially soon after entry into the body. Thus, some organisms produce PAMPs, which are not recognized by and may even inhibit TLR4. As only one example, Yersinia pestits produces PAMPs, which evade recognition by TLRs [7 ], and although TLR4 can be inferred to be essential for host defense against pathogenic bacteria [8 ] and for development of the sepsis syndrome [5 , 9 ], antagonists of LPS appear to have no evident impact, for better or worse, on the outcome of gram-negative infection [10 ].

The interaction of PAMP with TLR does not explain other putative functions of TLR in health and disease. For example, recognition of PAMP does not explain the etiology of the systemic inflammatory response syndrome (SIRS) or how activation of TLR could be essential to the pathogenesis of such "sterile conditions" as ischemia [11 ], atherosclerosis [12 ], osteoporosis, and obesity [13 ], in which no infection can be found. For example, Zhai and colleagues [11 ] reported that ischemic injury to the liver does not occur in mutant mice, which lack functional TLR4, and subsequently found that activation of TLR4 in this system is not mediated by LPS, the archtypic agonist for TLR4, as LPS inhibitors have no impact on the lesion (Jerzy Kupiec Weglinski, University of California, Los Angeles, CA, USA, personal communication).

Research we conducted about the question of how vascular disease arises during rejection of transplants appears unexpectedly to have offered some answers to these challenges. This research focused on heparan sulfate proteoglycan. Heparan sulfate is an acidic copolymer on cell surfaces and extracellular matrices. Among its many functions in physiology, heparan sulfate proteoglycan promotes the integrity of the endothelial barrier, protects against complement and oxidants, and inhibits coagulation [14 , 15 ]. Given these functions, we reasoned that if tissue damage, inflammation, or immunity were to compromise vascular heparan sulfate, vascular disease might ensue [15 , 16 ]. As a first step, we found that complement [16 ], neutrophils [17 ], T cells [18 ], and ischemic injury [19 ] cause heparan sulfate to be shed from endothelial cells. Accordingly, we reasoned that loss of heparan sulfate might explain the abnormal structure and function of blood vessels in acute injury, inflammation, and immune reactions [14 , 15 ].

Whether this speculation about loss of heparan sulfate and vascular disease is correct, this line of research led us to consider whether heparan sulfate shed from blood vessels might have biological properties. We questioned particularly whether heparan sulfate in soluble form might promote initial activation of T cells in viral infections and transplantation. Consistent with this possibility, Wrenshall et al. [20 , 21 ] found that heparan sulfate in soluble form promotes activation of T cells and does so by activating APC rather than on responding T cells. Kodaira et al. [22 ] showed that heparan sulfate induces the presentation of antigen and expression of costimulatory molecules by dendritic cells (DC) in the same way as does LPS. From these findings, we concluded that shedding of heparan sulfate might not only explain how ischemia and tissue injury help initiate adaptive immune responses. Still uncertain was how DC and macrophages recognize heparan sulfate.

The cloning of the TLR and characterization as sentinels for microbial substances [23 ] led us to explore the possibility that TLR might also recognize heparan sulfate. To addresses this possibility, we asked whether the responses of murine DC to heparan sulfate depended, to the same extent, on TLR4, as does the response to LPS [24 ]. Our studies revealed that heparan sulfate-like LPS induced expression of CD40, CD80, and CD86 and activation of NF-{kappa}B and p38 MAPK, but neither heparan sulfate nor LPS induced these changes in DC with nonfunctional or absent TLR4. Thus, responses to heparan sulfate depended on and were probably delivered by TLR4. Accordingly, we referred to heparan sulfate as an "endogenous agonist" [25 , 26 ]. Whether endogenous agonists such as heparan sulfate could generate biological responses and whether they function in physiology and pathophysiology were still uncertain.

To determine whether heparan sulfate can generate biological responses, we asked whether it can induce SIRS [27 ]. Following i.p. injection of heparan sulfate, wild-type mice had high levels of TNF-{alpha} in their blood and later died, both with the same kinetics as responses to LPS (Fig. 1 ) [28 ]. However, mutant mice with defective function or expression of TLR4 or CD14, a coreceptor in the TLR4 complex, showed no response to LPS (as expected) or heparan sulfate. This finding suggested that inflammatory events, such as trauma and drugs, which induce the shedding of heparan sulfate, might eventuate SIRS. However, most of our work described above had been conducted using heparan sulfate glycosaminoglycan chains, soluble saccharide cleaved from the proteoglycan core proteins of cell surfaces, and extracellular matrices. What might generate such chains in the inflammatory response syndrome or other conditions heparan sulfate might provoke?


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  		Figure 1. Activation of TLR 4 by heparan sulfate. This figure reviews some of the experimental evidence, showing that heparan sulfate might activate TLR4 and in doing so, account for such conditions as SIRS. (A) Testing heparan sulfate (HS) as an agonist for TLR4 in a defined model system. Human embryo kidney (HEK) 293 cells were stably transfected with expression vectors encoding murine TLR4 and myeloid differentiation protein-2 (MD2; TLR4/MD2) or TLR4, MD2, and CD14. Responses to TLR4 activators were measured by assay of a NF-{kappa}B-luciferase reporter gene [29 ]. The figure shows that heparan sulfate activates cells bearing TLR4 and that activation depends on expression of TLR4 and other components of the TLR4 receptor complex. Not shown are extensive controls [29 ]. (B) Induction of SIRS by heparan sulfate. C57BL/10SnJ (TLR4 wild-type) or C57BL/10ScN (TLR4-deficient) mice were injected with D-galactosamine plus heparan sulfate (2 mg) or LPS (5 µg), with or without Limulus anti-LPS factor (LALF), a protein that binds specifically to and neutralizes LPS. Positive or negative control injections consisted of D-galactosamine plus CpG DNA (a TLR9 agonist) or LALF or PBS. The figure shows survival; measurement of TNF-{alpha} yielded corresponding positive and negative results. Each group includes five animals. These results show that heparan sulfate can induce the systemic inflammatory response via TLR4. (C) Testing whether release of heparan sulfate from tissues might induce SIRS, we reasoned that if heparan sulfate can induce SIRS, then treatments that liberate endogenous heparan sulfate might do so. To test this idea, we first determined that administration of elastase, a protease that cleaves the protein core of heparan sulfate proteoglycan, causes shedding of heparan sulfate from various tissues (not shown). We then tested whether elastase might cause SIRS, shown in the figure. C57BL/10SnJ (TLR4 wild-type) and C57BL10/ScNCr (TLR4-deficient) mice were injected with D-galactosamine plus elastase (1.5 units), heparan sulfate, LPS, or CpG DNA (TLR9 agonist). Control mice were injected with D-galactosamine plus elastase, which had been inactivated by treatment with elastase inhibitor-1 or by boiling. The figure depicts survival; corresponding positive and negative results were observed with the measurement of TNF-{alpha}. (Figure adapted from ref. [30 ].)

 
Heparan sulfate is shed from cells by the action of proteases, which cleave the protein core, and heparanase and endoglycosidase, which cleave the saccharide chains, or both [31 , 32 ]. As complete cleavage of heparan sulfate by endoglycosidase abolishes the ability of heparan sulfate to stimulate TLR4 [21 , 24 ], we reasoned that proteases might play the key role in making heparan sulfate available to stimulate TLR. Consistent with this possibility, we found that injection of elastase into mice liberated heparan sulfate from the vicinity of blood vessels and triggered expression of costimulatory molecules by leukocytes in the spleen, but heat-inactivated elastase had no agonist effect on TLR4 [27 ]. Moreover, injection of elastase into the peritoneal cavity of mice caused the release of heparan sulfate and induced SIRS, nearly as effectively as heparan sulfate or LPS in normal mice, but had no impact on mice with defective or deficient TLR4 (Fig. 1) [27 ]. These results were consistent with the possibility that heparan sulfate or some other endogenous substance released by elastase could trigger SIRS by acting on TLR4.

As endogenous substances could potentially activate TLR4 and induce key pathological reactions, we questioned whether these substances might initiate inflammatory reactions, which over time, account for some of the chronic diseases that afflict modern societies. Some chronic conditions, such as atherosclerosis [12 ], type 2 diabetes [33 , 34 ], and asthma [30 ], had been linked with the tlr4 gene, but the basis for this connection was not known. To address that question, we examined various indices of well-being (body fat, bone density, and motor activity), which could be measured serially in wild-type mice and mutant mice with defective or deficient TLR4 or the coreceptor CD14, the genes for which are on separate chromosomes [13 ]. The wild-type mice and the mutant mice were comparably active; however, the wild-type mice gained weight progressively and lost bone density over time, and the mutant mice did not. This dramatic difference between mutations at distinct loci, strongly implicated the functioning of TLR4 in some of the most vexing, chronic conditions. In addition, the absence of any evidence of infection and the comparable levels of activity suggested that activation of TLR4 in the wild-type mice was probably triggered by endogenous substances rather than products of pathogenic bacteria. However, if endogenous substances as ubiquitous as heparan sulfate can stimulate TLR4 over long periods of time locally, what prevents widespread, spontaneous activation of TLR4?

To explain how TLR4 and endogenous agonists can exist on cell surfaces in the same place and time in normal physiology, we reasoned that TLR4 might be subject to control in one or more of three ways. First, heparan sulfate (or some other endogenous agonist) might not, as an intact substance, stimulate TLR4, but rather, a degradation product or modified form of heparan sulfate might do so. This mechanism had been postulated to control responses of TLR4 to hyaluronic acid [35 ]. Second, proteins or other substances (e.g., growth factors or fibronectin) naturally might sterically hinder or block interaction with TLR4 directly. Third, activation of TLR4 might be inhibited constitutively in some way, and activation might thus depend on release from inhibition.

To distinguish among these possibilities, we devised a model system, which would enable us to measure TLR4 activation [29 ]. HEK cells, which we found to be devoid of functional components of the TLR4 complex, were stably transfected with TLR4, MD2, and CD14. The cells were also transfected with a reporter, which would allow measurement of NF-{kappa}B activation. Stimulation of these cells with LPS or with heparan sulfate activated the reporter gene, allowing measurement of receptor activity (Fig. 1) . To recapitulate the conditions we envisioned might exist in tissues, we embedded the TLR4 reporter cells in that matrix, which had been generated by endothelial cells. The matrix produced by endothelial cells is rich in heparan sulfate proteoglycan and thus, is a model substrate for cells found in tissues. The cells embedded in matrix did not respond to TLR4 or to LPS. However, exposure of the cells to low concentrations of elastase restored full responses to heparan sulfate and to LPS. Furthermore, slightly higher concentrations of elastase activate TLR4 signaling without addition of an agonist. In this case, elastase relieves suppession of TLR4 signaling and releases an endogenous TLR4 activator, likely heparan sulfate proteoglycan, from the matrix.

These results suggested that under normal, resting conditions, some and maybe many TLR4-expressing cells do not respond readily to TLR4 agonists, but rather, the cells must be released from constitutive suppression. Our experiments suggest proteases acting in matrix-relieve suppression of TLR4. Consistent with this possibility, we found that treatment of mice with small amounts of elastase—too small to generate endogenous agonist activity as described above—allowed much more robust responses to subsequent administration of LPS.

The constitutive inhibition of TLR4 signaling and the manner of release from inhibition suggest one solution to surveillance for microbial pathogens [25 ]. Microorganisms, which induce tissue injury, trigger the release and/or activation of proteases through a variety of mechanisms, such as the activation of the complement or coagulation cascades. Proteases, in turn, release TLR4 from constitutive suppression. So released, TLR4 can respond to endogenous agonists or to PAMPs. By this mechanism, the immune system is relieved of the need to recognize microbial substances specifically but rather, can respond to any organism, which can induce tissue injury or local ischemia. Consistent with this concept, we have observed some facets of innate immunity to be activated by proteases in invertebrate animals (A. H. Tang, unpublished observations).

The action of endogenous agonists for TLR and the control of TLR activation described above explain some of the important challenges met by the innate immune system. To the extent that tissue injury generates agonists for TLR, such as soluble heparan sulfate, innate immunity can be triggered and recruited to sites of infection, even if the infecting organism produces PAMP with little or no agonist activity (or no PAMP at all). Innate immunity can be recruited to respond to toxins, metals, foreign bodies, and other "noninfectious" threats, which have no intrinsic PAMP. In addition, innate immunity has the means to control or limit activity to sites where injury is ongoing and simultaneously suppresses injury in adjoining, healthy tissue, thus preventing a situation in which the protective response is worse than the disease against which it is protecting.

We should not want to close this discussion without considering the limitations of our views about endogenous agonists and the control of TLR function. Our concepts work well in cultured cells and in animal models of disease. However, we have not tested our ideas in actual diseases or conditions thought to be mediated by the TLRs. Until such testing is performed, our work should be taken as an alternative to the canonical view that exogenous substances trigger TLRs, which are unfettered in their ability to respond to such stimulation.

ACKNOWLEDGEMENTS

This work described in this communication was supported by grants from the National Institutes of Health (AI53733, HL079067, and GM069922).

Received December 22, 2006; revised April 13, 2007; accepted April 17, 2007.

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