Originally published online as doi:10.1189/jlb.0304127 on June 3, 2004

Published online before print June 3, 2004

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(Journal of Leukocyte Biology. 2004;76:514-519.)
© 2004 by Society for Leukocyte Biology

Endogenous ligands of Toll-like receptors

Min-Fu Tsan^*,,1 and Baochong Gao^*,

^* Research Service, VA Medical Center, Washington, DC;
Department of Medicine, Georgetown University, Washington, DC; and
Department of Medicine, George Washington University, Washington, DC

¹ Correspondence: Mid-Atlantic Regional Office (10R), Office of Research Oversight, Department of Veterans Affairs, 50 Irving Street, NW, Washington, DC 20422. E-mail: min-fu.tsan2{at}med.va.gov

TOP ABSTRACT INTRODUCTION TLRs ENDOGENOUS LIGANDS OF TLRs ENDOGENOUS LIGANDS VERSUS... CONCLUSION REFERENCES

 
Extensive work has suggested that a number of endogenous molecules such as heat shock proteins (hsp) may be potent activators of the innate immune system capable of inducing proinflammatory cytokine production by the monocyte-macrophage system and the activation and maturation of dendritic cells. The cytokine-like effects of these endogenous molecules are mediated via the Toll-like receptor (TLR) signal-transduction pathways in a manner similar to lipopolysaccharide (LPS; via TLR4) and bacterial lipoproteins (via TLR2). However, recent evidence suggests that the reported cytokine effects of hsp may be a result of the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) being responsible for the putative TLR ligands of hsp include failure to use highly purified hsp free of LPS contamination; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS. Whether other reported putative endogenous ligands of TLR2 and TLR4 are a result of contamination of pathogen-associated molecular patterns is not clear. It is essential that efforts should be directed to conclusively determine whether the reported putative endogenous ligands of TLRs are a result of the endogenous molecules or of contaminant(s), before exploring further the implication and therapeutic potential of these putative TLR ligands.

Key Words: endotoxin • danger signal • pathogen-associated molecular patterns

TOP ABSTRACT INTRODUCTION TLRs ENDOGENOUS LIGANDS OF TLRs ENDOGENOUS LIGANDS VERSUS... CONCLUSION REFERENCES

 
Toll-like receptors (TLRs), the mammalian homologues of the Drosophila Toll protein, play a crucial role in the innate host defense against invading microorganisms by recognizing conserved motifs of microbial origin, also called pathogen-associated molecular patterns (PAMPs) [¹ , ² ]. However, there has been a plethora of reports in recent years suggesting that a number of endogenous molecules may also be potent activators of the innate immune system [³ , ⁴ ]. These endogenous molecules are shown to be capable of inducing the release of proinflammatory cytokines from the monocyte-macrophage system, and the activation and maturation of dendritic cells (DCs). In addition, the cytokine-like effects of these endogenous molecules are mediated via the TLR signal-transduction pathways [^{5 6 7 8 9 10 11 12 13 14 15} ]. Thus, the term, "endogenous ligands of TLRs," has been denoted for these molecules to distinguish them from the primary role of TLRs recognizing exogenous molecules of microbial origin [⁴ , ⁵ ]. The purpose of this brief review is to critically evaluate the reported putative, endogenous ligands of TLRs, with particular emphasis on the question of whether the reported cytokine effects are in fact a result of these endogenous molecules or of the contamination by exogenous molecules of microbial origin.

TOP ABSTRACT INTRODUCTION TLRs ENDOGENOUS LIGANDS OF TLRs ENDOGENOUS LIGANDS VERSUS... CONCLUSION REFERENCES

 
TLRs are members of the interleukin-1 receptor (IL-1R) superfamily and share significant homology in their cytoplasmic regions, e.g., the Toll/IL-1R (TIR) domain [¹ , ² ]. So far, 10 TLRs, TLR1–TLR10, have been identified. Structurally, TLRs are characterized by the presence of a leucine-rich repeat domain in their extracellular regions and a TIR domain in the intracellular regions. Based on the amino acid sequence and genomic structure, TLRs can be divided into five subfamilies: TLR2, TLR3, TLR4, TLR5, and TLR9. The TLR2 subfamily is composed of TLR1, TLR2, TLR6, and TLR10, and the TLR9 subfamily is composed of TLR7, TLR8, and TLR9. TLR1 and TLR6 form heterodimers with TLR2 [² ].

TLR ligands
In 1998, TLR4 was identified as the signal transducer for lipopolysaccharide (LPS), a major cell-wall component of Gram-negative bacteria [¹⁶ ]. Since then, TLRs have been shown to recognize and mediate signals for a wide range of microbial components: TLR1 (in association with TLR2, TLR1/2) for triacyl lipopeptides [¹⁷ ]; TLR2 for lipoproteins and peptidoglycans [¹⁸ ]; TLR3 for double-stranded RNA [¹⁹ ]; TLR5 for flagellin [²⁰ ]; TLR6 (in association with TLR2, TLR2/6) for diacyl lipopeptides [²¹ ]; TLR7 for single-stranded RNA [²² ], and TLR9 for nonmethylated CpG DNA [²³ ]. TLR7 also appears to recognize several synthetic compounds that are structurally related to nucleic acids such as imidazoquinolines [²⁴ ]. In human, but not in mouse, TLR8 also appears to recognize the imidazoquinoline, resiquimod (R-848) [²⁵ ]. No ligand has been identified for TLR10 so far. Thus, TLRs appear to recognize conserved molecular features of bacteria, fungi, and viruses. Interaction of TLRs with PAMPs indicates the presence of infection and initiates signaling cascades leading to inflammatory and immune responses [² , ^{26 27 28} ].

TLR signaling
Despite divergent PAMP ligands, TLRs, with the exception of TLR3, share a common signaling pathway via the adaptor molecule, MyD88, which has a TIR domain in its C-terminal region and a death domain (DD) in its N-terminal region [² , ^{26 27 28} ]. Upon stimulation, TLRs recruit MyD88 through interaction of their respective TIR domains. The DD of MyD88 then binds the DD of IL-1R-associated kinase, and the signal is propagated via tumor necrosis factor (TNF) receptor-associated factor-6, leading to the activation of nuclear factor (NF)-B and mitogen-activated protein kinases and the transcription of immunologically relevant genes [² , ^{26 27 28} ]. Recently, a second TIR-containing adaptor protein, TIR-associated protein (TIRAP)/MyD88-adaptor-like, was identified to be involved in the MyD88-dependent pathways of TLR1/2, TLR2/6, and TLR4 but not other TLRs [²⁹ , ³⁰ ]. Conversely, the TLR3 ligand, double-stranded RNA is able to induce NF-B activation in MyD88 knockout (KO) mice, suggesting that TLR3 signaling is independent of MyD88 [¹⁹ ].

In addition to the common MyD88-mediated signaling pathway, a MyD88-independent pathway has been identified that involves a third TIR-containing adaptor molecule, TIR domain-containing adaptor-inducing interferon-ß (IFN-ß; TRIF) [³¹ ], which is essential for the TLR3 and TLR4 signaling, leading to the induction of transcription factor, IFN regulatory factor 3, and the subsequent production of IFN-ß and the activation and maturation of DCs [³² ]. Recently, a fourth TIR-containing adaptor molecule, TRIF-related adaptor molecule (TRAM), has been shown to be involved specifically in TLR4- but not TLR3-mediated, MyD88-independent IFN-ß production [³³ ]. Thus, TIRAP, TRIF and TRAM provide specificities for TLR-mediated signaling.

Undoubtedly, more TLR ligands and signaling pathways will be identified in the future. For more detailed description of TLRs, the readers are referred to recent, excellent reviews of the subject [² , ^{26 27 28} , ³⁴ ].

TOP ABSTRACT INTRODUCTION TLRs ENDOGENOUS LIGANDS OF TLRs ENDOGENOUS LIGANDS VERSUS... CONCLUSION REFERENCES

 
Extensive work in the past 10 years has suggested that heat shock proteins (hsp) may be potent activators of the innate immune system [³ , ³⁵ ]. hsp such as Hsp60, Hsp70, and gp96 (the endoplamic reticulum Hsp90) from a variety of sources, including purified preparations from bacterial [³⁶ , ³⁷ ] and mammalian [⁷ , ³⁸ , ³⁹ ] sources as well as recombinant bacterial [^{40 41 42 43 44 45} ] and human [⁵ , ⁶ , ⁴³ , ^{46 47 48 49 50 51} ] products, are shown to induce the production of proinflammatory cytokines such as TNF-, IL-1, IL-6, and IL-12 and the release of nitric oxide (NO) and C–C chemokines by monocytes, macrophages, and DCs. They also induce the maturation of DCs, as demonstrated by the up-regulation of major histocompability complex classes I and II molecules and costimulatory molecules such as CD80 and CD86 [³⁸ , ³⁹ , ⁴⁴ , ⁵² ]. These hsp cytokine effects, as compared with their molecular chaperone function, are unique in that they require no hsp-associated peptides, no adenosine 5'-triphosphate (ATP) hydrolysis, no cofactors, and no protein complex assembly [³⁵ ]. A new term, "chaperokine," has been coined for hsp to indicate their dual functions as molecular chaperones and cytokines [⁴⁷ ].

Similar cytokine effects have also been reported for a number of molecules of mammalian origin, including fibrinogen [⁸ ], surfactant protein-A [⁹ , ⁵³ ], extra domain A of fibronectin [¹⁰ , ⁵⁴ ], heparan sulfate [¹¹ , ⁵⁵ ], oligosaccharide of hyaluronan (soluble hyaluronan) [¹² , ⁵⁶ , ⁵⁷ ], ß-defensin 2-lymphoma antigen idiotype sFv fusion protein [¹³ ], high-mobility group box 1 (HMGB1) protein [¹⁴ ], and mRNA [¹⁵ ]. In 2000, using macrophages from C3H/HeJ mice with Tlr4 gene-point mutation, Ohashi et al. [⁵ ] demonstrated that the cytokine effects of recombinant human Hsp60 (rhHsp60) were dependent on TLR4, suggesting that Hsp60 might be a TLR4 ligand. As Hsp60 is of mammalian origin, the term endogenous ligand was designated for this group of TLR ligands to distinguish them from the exogenous ligands of microbial origin [⁴ , ⁵ ]. Since then, using TLR4 mutant mice (C3H/HeJ with point mutation or C57BL/10ScCr with gene deletion), TLR2 KO mice, and/or fibroblasts transfected with TLR2, TLR3, or TLR4 cDNA, it has been shown that fibrinogen [⁸ ], surfactant protein-A [⁹ ], fibronectin extra domain A [¹⁰ ], heparan sulfate [¹¹ , ⁵⁸ ], soluble hyaluronan [¹² ], and ß-defensin 2 [¹³ ] are endogenous ligands for TLR4; Hsp60 [⁴⁵ , ⁴⁹ ], Hsp70 [⁶ , ⁵⁰ , ⁵¹ ], gp96 [⁷ ], and HMGB1 protein [¹⁴ ] are endogenous ligands for TLR2 and TLR4; and mRNA is an endogenous ligand for TLR3 (Table 1 ).

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Table 1. Endogenous Ligands of TLRs

The identification of endogenous ligands for TLRs capable of inducing not only the innate immune response but also the adaptive immune system through induction of costimulatory molecules in antigen-presenting cells (APCs), e.g., DCs, necessitates the need to revise the original, self-nonself, immune-surveillance hypothesis [⁵⁹ ]. The "danger" theory proposes that the immune system has evolved primarily to recognize the danger signals rather than the nonself signals [⁶⁰ ]. For example, the presence of hsp potentially signals tissue damage or cellular stress to the immune system [⁴⁶ ]. More recently, the surveillance model proposes that the immune system recognizes not only the endogenous and exogenous molecules but also the degradation products of endogenous macromolecules such as heparan sulfate and polysaccharide fragments of hyaluronan, which indicate tissue injury, infection, and tissue remodeling [⁶¹ ].

The recognition of these endogenous molecules by TLRs and the subsequent inflammatory and immune responses may have important physiological, immunological, and pathological implications [³ , ⁴ , ³⁵ ]. The induction of proinflammatory cytokines by Hsp60 and Hsp70 may contribute to the pathogenesis of a number of autoimmune diseases and chronic inflammation such as type I diabetes [⁶² , ⁶³ ], Crohn’s disease [⁶⁴ ], juvenile chronic arthritis [⁶⁵ ], and atherosclerosis [⁶⁶ , ⁶⁷ ]. Chlamydial Hsp60 frequently colocalizes with human Hsp60 in macrophages of atherosclerotic plaques [⁴² ]. Induction of proinflammatory cytokine release from macrophages by chlamydial Hsp60 would provide a potential mechanism by which chlamydial infections may promote atherogenesis and precipitate acute ischemic events [⁴² , ⁴³ ]. The activation and maturation of DCs by gp96 may be responsible for the gp96-induced tumor immunity by inducing the innate and adaptive immune responses [⁶⁸ ]. Likewise, the recognition of degradation products of macromolecules, such as fibronectin extra domain A, heparan sulfate, and soluble hyaluronan by TLR4, signals tissue injuries in the absence of infection and the need for tissue repair [⁶¹ ]. Conversely, the recognition of endogenous molecules such as fibrinogen and surfactant protein-A by TLR4 is of considerable concern. Fibrinogen is normally present in circulation at high concentrations, e.g., 2–4 mg/ml. Monocytes, DCs, and sinusoidal macrophages, such as hepatic Kupffer cells and splenic macrophages, are constantly exposed to fibrinogen. Likewise, surfactant protein-A is normally present in lung alveoli, where alveolar macrophages reside. A life-long, continuous exposure of immune cells to these TLR ligands may be deleterious to the host.

TOP ABSTRACT INTRODUCTION TLRs ENDOGENOUS LIGANDS OF TLRs ENDOGENOUS LIGANDS VERSUS... CONCLUSION REFERENCES

 
The reported cytokine effects of these putative endogenous ligands are similar to the effects of LPS and bacterial lipoproteins [³ , ⁴ , ³⁵ ]. As shown in Table 1 , evidence for the endogenous ligands of TLRs was derived using recombinant products, purified native molecules, or purified fragments of macromolecules. As recombinant products are produced by genetically engineered Escherichia coli, the final preparations may be contaminated with bacterial products. Likewise, purified preparations are also frequently contaminated with bacterial cell-wall products such as LPS and lipoproteins [⁶⁹ ]. With the exception of mRNA, which was reported as the endogenous ligand for TLR3, all other reported endogenous ligands are for TLR2 and/or TLR4.

Ample examples exist in the literature, demonstrating how contaminants can lead to misleading conclusions. For example, in 1998, using the commercially available LPS preparation, it was first reported that TLR2 mediated the LPS-induced activation of NF-B and could be the long sought-after LPS signal transducer [⁷⁰ ]. However, the commercially available LPS preparation was later shown to be contaminated with bacterial lipoproteins [⁷¹ ] and that TLR4, instead of TLR2, was the signal transducer for LPS [¹⁶ , ⁷² ]. Thus, failure to recognize the presence of lipoproteins in the commercially available LPS preparation, led to the erroneous attribution of lipoprotein signal-transducer TLR2 as the LPS signal transducer [⁷⁰ , ⁷³ ].

Investigators are cognizant of the possibility of contamination, particularly LPS, and have attempted to rule out the possibility of LPS contamination being responsible for the observed cytokine effects of these putative endogenous ligands of TLRs. However, as shown in Table 1 , the exact amount of LPS present in most preparations was not quantified. Most studies have used two criteria: First, LPS is resistant to heat inactivation [^{7 8 9 10} , ¹³ , ³⁷ , ⁴⁴ , ⁴⁶ , ⁴⁹ , ⁵⁰ ], and second, LPS effects are inhibitable by polymyxin B [^{7 8 9 10} , ^{12 13 14} , ³⁷ , ⁴⁴ , ⁴⁹ , ⁵⁰ ]. Other, less frequently used criteria include other LPS inhibitors such as lipid IVa [⁴⁷ ], E5564 [¹⁰ ], LPS [¹³ , ³⁸ , ³⁹ ], or lipid A [⁵⁰ ] from Rhodopseudomonas spheroids and Limulus anti-LPS factor [¹¹ ] and protease digestion [¹³ , ¹⁴ , ³⁸ ]. As the observed cytokine effects were heat-sensitive, not inhibitable or only partially inhibitable by polymyxin B, not inhibitable by other LPS inhibitors, or inhibitable by protease digestion, it was concluded that the observed cytokine effects could not have been a result of LPS contamination. However, doubts about these criteria have been raised. Wallin et al. [³ ] noted that highly purified murine liver Hsp70 had no cytokine effects even at concentrations as high as 200–300 µg/ml. Conversely, a LPS-contaminated preparation at Hsp70 concentrations as low as 50–100 ng/ml caused cytokine effects that were heat-sensitive and were not inhibitable by polymyxin B.

Recent studies using hsp preparations essentially free of LPS suggest that the previously reported cytokine function of hsp may be a result of contaminants [^{74 75 76 77 78} ]. Bausinger et al. [⁷⁴ ] reported that LPS-free rhHsp70 did not induce the activation of DCs. Gao and Tsan [⁷⁵ , ⁷⁶ ] demonstrated that LPS was heat-sensitive (Fig. 1 ) and that the ability of commercially available rhHsp70 to induce TNF- production was entirely a result of the contaminating LPS [⁷⁵ ], and that of rhHSP60 was a result of contamination by LPS as well as LPS-associated molecules [⁷⁶ ]. Reed et al. [⁷⁷ ] reported that the activation of NF-B and the production of NO by gp96 were a result of LPS contamination. It is important that all these investigators demonstrated that these highly purified, essentially LPS-free hsp retained their normal molecular chaperone function or ATPase activity [^{74 75 76 77} ]. Thus, failure of Hsp60, Hsp70, and gp96 to induce cytokine or NO production by macrophages or to activate APCs was not a result of defective hsp as a result of purification. Recent studies have demonstrated the in vivo activation of DCs by transgenic expression of cell-surface gp96 or by the administration of syngeneic, gp96-secreting fibroblasts in mice [⁷⁹ , ⁸⁰ ]. These studies have avoided the potential of LPS contamination. However, it is not clear whether the observed in vivo activation of the innate immune system was a result of a direct effect of gp96 on DCs or was indirectly mediated by other cellular mediators.

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Figure 1. Effect of heat inactivation on endotoxin activity and TNF--inducing activity of LPS. A stock solution of LPS at 4 ng/ml was heated in a boiling water bath for 1 h. (A) Endotoxin activities of the nonheated LPS and heated LPS were determined using the Limulus amebocyte lysate assay. (B) Murine macrophages were treated with LPS or heated LPS at the indicated concentrations for 4 h. TNF- concentrations in media were then determined. Values represent means ± SD of three experiments. *, P < 0.05 (vs. nonheated LPS). (Reproduced from ref. [76 ] with the permission of the publisher.)

The fact that LPS is sensitive to heat inactivation [⁷⁵ , ⁷⁶ , ⁸¹ , ⁸² ] has not been widely appreciated. Most investigators are not aware that macrophages are extremely sensitive to LPS, which at a concentration of 0.1–0.2 ng/ml, is sufficient to maximally induce TNF- release from murine macrophages [⁷⁵ ]. However, most studies used LPS at concentrations ranging from 10 to 500 ng/ml to test for heat sensitivity [^{7 8 9 10} , ¹³ , ³⁷ , ⁴⁴ , ⁴⁶ , ⁴⁸ , ⁵⁰ ]. At these concentrations, even if heat treatment inactivated 99% of the LPS, there would still be sufficient, residual LPS to induce TNF- release, giving the impression that LPS was heat resistant. Thus, unless one uses an LPS concentration similar to the LPS concentration present in the preparation one is testing, the result could be misleading.

In addition, although LPS may be the most frequent contaminant, non-LPS bacterial cell-wall contaminant(s) capable of inducing proinflammatory cytokines such as lipoproteins may also contribute to the reported cytokine effects. Gao and Tsan [⁷⁶ ] showed that 50% of the TNF--inducing activity of the commercially available rhHsp60 was a result of non-LPS contaminant(s), which was heat-sensitive but not inhibitable by polymyxin B. The presence of non-LPS contaminant(s) could explain previous reports that the observed cytokine effects were not inhibitable or only partially inhibitable by polymyxin B [^{7 8 9 10} , ^{12 13 14} , ³⁷ , ⁴⁴ , ^{46 47 48 49 50} ]. None of these reports attempted to rule out the possibility of bacterial cell-wall contaminants other than LPS, even when the endogenous molecules were reported as the TLR2 ligands [⁷ , ¹⁴ , ⁴⁵ , ^{49 50 51} ].

It is not clear, in addition to hsp, which of the reported putative endogenous ligands of TLRs is a result of contaminant(s). As shown in Table 1 , the preparation of surfactant protein-A studied contained 140 pg LPS per µg of the surfactant protein [⁹ ]. With the concentrations of 2.5–20 µg/ml surfactant protein-A tested [⁹ ], the final concentrations of LPS (350–2800 pg/ml) are sufficient to account for the observed cytokine effects. Thus, the observed cytokine effects of surfactant protein-A are at least in part a result of the contaminating LPS.

TOP ABSTRACT INTRODUCTION TLRs ENDOGENOUS LIGANDS OF TLRs ENDOGENOUS LIGANDS VERSUS... CONCLUSION REFERENCES

 
Extensive work has suggested that a number of endogenous molecules such as hsp may be potent activators of the innate immune system capable of inducing proinflammatory cytokine production by the monocyte-macrophage system and the activation and maturation of DCs. The cytokine-like effects of these endogenous molecules are mediated via TLR signal-transduction pathways in a manner similar to LPS (via TLR4) and bacterial lipoproteins (via TLR2). However, recent evidence suggests that the reported cytokine effects of hsp may be a result of the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) being responsible for the putative TLR ligands of hsp include: failure to use highly purified hsp free of LPS contamination; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS [³⁵ ]. Whether other reported putative, endogenous ligands of TLR2 and TLR4 are a result of contaminating, pathogen-associated molecular patterns is not clear. Before exploring further the implication and therapeutic potential of these putative TLR ligands, it is essential that efforts should be directed to conclusively determine whether the reported putative endogenous ligands of TLRs are a result of the endogenous molecules or of contaminant(s).

 
The Medical Research Service, Office of Research and Development, Department of Veterans Affairs, supported this work.

Received March 4, 2004; revised April 27, 2004; accepted April 30, 2004.

TOP ABSTRACT INTRODUCTION TLRs ENDOGENOUS LIGANDS OF TLRs ENDOGENOUS LIGANDS VERSUS... CONCLUSION REFERENCES

 

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