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Originally published online as doi:10.1189/jlb.1104636 on February 22, 2005

Published online before print February 22, 2005
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(Journal of Leukocyte Biology. 2005;77:886-892.)
© 2005 by Society for Leukocyte Biology

The expression and roles of Toll-like receptors in the biology of the human neutrophil

Lisa C. Parker1, Moira K. B. Whyte, Steven K. Dower and Ian Sabroe

Academic Units of Respiratory Medicine and Cell Biology, Section of Functional Genomics, Division of Genomic Medicine, University of Sheffield, United Kingdom

1Correspondence: Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital (M Floor), Sheffield, S10 2JF, UK. E-mail: l.c.parker{at}sheffield.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 TOLL-LIKE RECEPTORS (TLRs):...
 TLR-INDUCED NEUTROPHIL...
 TLR-INDUCED NEUTROPHIL SURVIVAL
 RECENT UPDATES FROM THE...
 CONCLUDING REMARKS
 REFERENCES
 
Neutrophils are amongst the first immune cells to arrive at sites of infection, where they initiate antimicrobial and proinflammatory functions, which serve to contain infection. Sensing and defeating microbial infections are daunting tasks as a result of their molecular heterogeneity; however, Toll-like receptors (TLRs) have emerged as key components of the innate-immune system, activating multiple steps in the inflammatory reaction, eliminating invading pathogens, and coordinating systemic defenses. Activated neutrophils limit infection via the phagocytosis of pathogens and by releasing antimicrobial peptides and proinflammatory cytokines and generating reactive oxygen intermediates. Through the production of chemokines, they additionally recruit and activate other immune cells to aid the clearance of the microbes and infected cells and ultimately, mount an adaptive immune response. In acute inflammation, influx of neutrophils from the circulation leads to extremely high cell numbers within tissues, which is exacerbated by their delayed, constitutive apoptosis caused by local inflammatory mediators, potentially including TLR agonists. Neutrophil apoptosis and safe removal by phagocytic cells limit tissue damage caused by release of neutrophil cytotoxic granule contents. This review addresses what is currently known about the function of TLRs in the biology of the human neutrophil, including the regulation of TLR expression, their roles in cellular recruitment and activation, and their ability to delay apoptotic cell death.

Key Words: inflammation • TLR • leukocyte • lipopolysaccharide


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
TOLL-LIKE RECEPTORS (TLRs):...
 TLR-INDUCED NEUTROPHIL...
 TLR-INDUCED NEUTROPHIL SURVIVAL
 RECENT UPDATES FROM THE...
 CONCLUDING REMARKS
 REFERENCES
 
Neutrophils play an essential role in infection and innate immunity, providing early defense against invading microorganisms. They comprise approximately two-thirds of peripheral blood leukocytes and transit rapidly to sites of infection, where they limit infection and allow recruitment and activation of other immune cells through the release of inflammatory mediators and antimicrobial products, resulting in pathogen clearance and ultimately, in the initiation of an adaptive immune response [1 ]. Excessive or inappropriate neutrophil activation can result in inflammation and severe tissue damage and thus contribute to the pathology of a variety of noninfectious diseases, such as rheumatoid arthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome [2 , 3 ].


   TOLL-LIKE RECEPTORS (TLRs): EXPRESSION AND SIGNALING
TOP
 ABSTRACT
 INTRODUCTION
 TOLL-LIKE RECEPTORS (TLRs):...
TLR-INDUCED NEUTROPHIL...
 TLR-INDUCED NEUTROPHIL SURVIVAL
 RECENT UPDATES FROM THE...
 CONCLUDING REMARKS
 REFERENCES
 
The innate-immune system is highly developed in its ability to discriminate between self and foreign pathogens, a process that relies, to a great extent, on an evolutionary conserved family of proteins, the TLRs [4 ]. Ten human TLRs have been identified so far, the targets of which are predominantly pathogen-associated molecular patterns (PAMPs), a limited set of conserved molecular patterns that are unique to microbes [5 ]. Identification of the agonists activating specific TLRs can be difficult, as the biological preparations used to probe TLR function are often impure. This has led to considerable confusion, as illustrated by data suggesting that most lipopolysaccharides (LPSs) activate TLR2, heat shock proteins (HSPs) 60 and 70 activate TLR2 and TLR4, and peptidoglycan (PGN) activates TLR2, responses now shown to be potentially mediated by contaminants within the individual preparations: lipoproteins in LPS [6 ], LPS in HSPs (reviewed in ref. [7 ]), and lipoteichoic acids (LTAs) in PGN [8 ].

TLR1, -2, -4, -5, and -6 are expressed on the cell surface, where they specialize in the recognition of bacterial products, including bacterial lipoproteins and LTAs (TLR2 as a heterodimer with TLR1 or TLR6), LPS (TLR4), or flagellin (TLR5) [9 ]. In phagocytic cells, there is evidence that these receptors are also recruited to the phagosome upon ligand-driven activation [10 , 11 ]. TLR3, -7, -8, and -9 are localized to intracellular compartments [12 13 14 ] and specialize in viral detection or the recognition of nucleic acids, including double-stranded DNA (TLR3), single-stranded viral RNA (TLR7), or the unmethylated CpG DNA of bacteria and viruses (TLR9) [9 ]. Human neutrophils express mRNA for all the TLRs, except TLR3 [15 ], and agonists of all the expressed TLRs elicit inflammatory responses in resting neutrophils [15 16 17 ], except for CpG, which requires granulocyte macrophage-colony stimulating factor (GM-CSF) pretreatment to enable responses [15 , 18 ]. Additionally, bacterial DNA can activate neutrophils in a TLR9- and CpG-independent manner by a mechanism yet to be identified [19 ]. Coreceptors at the cell membrane may also influence signaling, and neutrophils show high constitutive and inducible levels of the integrin CD11b/CD18 [20 ], which has been shown to contribute to TLR4 signaling in monocytic cells [21 ]. Signaling is also facilitated in the neutrophil, as in other cells, by lipid rafts [22 ].

Stimulation of the TLRs triggers complex signaling pathways containing branches that are common to all the TLRs and others that are selectively activated, which have the potential to tailor immune responses to pathogens (reviewed in refs. [23 , 24 ]). The prototypic pathway, principally dissected in monocytic cells, involves association of the intracellular Toll-interleukin-1 receptor (IL-1R; TIR)-signaling domain with the adaptor molecule MyD88 (one of a family of five adaptors; ref. [25 ]), which recruits IL-1R-associated kinase (IRAK)-4, allowing association and phosphorylation of IRAK-1, which in turn, recruits tumor necrosis factor (TNF) receptor-associated factor 6. From this signaling complex, downstream cascades ultimately lead to activation of nuclear factor (NF)-{kappa}B, a classical, proinflammatory gene transcription regulator [23 , 26 ]. Stimulation of TLRs also typically leads to activation of the mitogen-activated protein kinases (MAPKs) p38, extracelluar signal-regulated kinase, and c-jun-terminal kinase (JNK) by pathways that remain to be fully characterized [23 , 27 28 29 ] and activation of phosphoinositide-3 kinase (PI-3K) [30 , 31 ]. In keeping with the neutrophil expression of TLR4 [20 ] and the role of the neutrophil in innate immunity, a large body of literature reports LPS induction of NF-{kappa}B [32 , 33 ] and the MAPKs [30 , 34 35 36 37 ]. Although it is easy to speculate that actions of TLRs on neutrophils will also depend on the common adaptor MyD88, it has recently been shown that MyD88 and a second adaptor MyD88 adaptor-like/TIR domain-containing adaptor protein are essential for LPS-induced NF-{kappa}B activation and cytokine production in human fibroblasts and endothelial cells. In contrast, neither adaptor is absolutely required for these same functions in the primary human macrophage [38 ]. These data demonstrate a complexity in human myeloid and nonmyeloid cells that was not predicted based on previous work. In addition, it has recently been shown that LPS can activate MyD88-independent induction of antiviral genes in neutrophils, an effect of LPS also observed in monocytes; however, in contrast to the signaling pathways in monocytic cells, this does not involve autocrine activation via induction of interferon-ß [39 ]. The picture is further complicated by evidence that reactive oxygen species generation may also be important in the activation of TLR4-dependent signaling in the neutrophil [40 ]. An area that is starting to be explored is the ability of LPS to induce JNK activation in adherent but not suspended neutrophils, leading to the release of the chemokine monocyte chemoattractant protein-1, an activated protein-1-dependent gene product that is important for monocyte recruitment [30 ]. Thus, the ability of LPS to activate distinct responses in adherent and suspended neutrophils may have crucial implications for controlling neutrophil responses at sites of infection within tissues.


   TLR-INDUCED NEUTROPHIL ACTIVATION
TOP
 ABSTRACT
 INTRODUCTION
 TOLL-LIKE RECEPTORS (TLRs):...
 TLR-INDUCED NEUTROPHIL...
TLR-INDUCED NEUTROPHIL SURVIVAL
 RECENT UPDATES FROM THE...
 CONCLUDING REMARKS
 REFERENCES
 
Activation of TLRs by PAMPs facilitates neutrophil recruitment by up-regulation of endothelial adhesion molecule expression through activation of TLRs on the endothelial cells themselves or indirectly, via cytokine release from other tissue cells such as macrophages [41 ]. Local generation of chemokines in response to infection, triggered in part by TLR-mediated activation of macrophages [42 ], epithelia [43 , 44 ], and endothelial cells [44 ], enables tight adhesion (and potentially selective recruitment) of neutrophils and provides directional migration cues. It is logical to suppose that TLR activation might alter neutrophil trafficking, potentially to localize neutrophils to sites of inflammation. In keeping with that hypothesis, neutrophils activated with LPS or bacteria show loss of IL-8-binding capacity [45 ] and down-regulation of the IL-8Rs, CXC chemokine receptor 1 (CXCR1) and CXCR2 [46 47 48 ]. Typically, neutrophils also show LPS-induced down-modulation of chemokine signaling (measured by intracellular calcium flux) and decreased IL-8-directed chemotaxis [47 ]. The magnitude of these effects remains under investigation, but it appears that although IL-8 causes internalization and subsequent re-expression of CXCR1 and -2 [49 ], LPS appears to cause a protease-dependent loss of CXCR1 and -2 from the cell surface [47 ]. Work from our group using purified human neutrophils (presented at the Society for Leukocyte Biology’s 37th Annual Meeting [50 ] and manuscript in submission) found that selective TLR agonists predominantly induced down-regulation of CXCR2, the primary neutrophil receptor involved in regulation of recruitment. We also found that loss of CXCR2 was not associated with complete failure of chemotaxis to IL-8. Work by Fan and Malik [51 ] also showed that TLR4 activation could cause down-regulation of the G protein receptor kinases, which are involved in CXCR desensitization and consequently, enhance neutrophil responses to chemokines. Thus, TLR activation regulates chemokine receptor expression and function in neutrophils and presumably facilitates recruitment and localization of these cells to sites of infection and inflammation, but the mechanism involved and the final consequences are complex. Further complicating this picture, many other inflammatory mediators, also present at sites of infection (e.g., C5a, formylated bacterial peptides), also regulate neutrophil chemokine receptors in complex patterns [49 , 52 53 54 55 ].

Once at the site of infection, neutrophils respond by releasing antimicrobial peptides, generating reactive oxygen intermediates, and secreting cytokines and chemokines, effectively eliminating invading microorganisms. Many of these responses have also been shown to occur following TLR activation [15 16 17 , 46 , 56 , 57 ]. The majority of such work has used LPS and thus focused on TLR4 activation; however, it is now clear that most commercial preparations contain small amounts of contaminating bacterial lipoproteins that are potentially potent agonists for TLR2. Repurification of commercial LPS by extensive phenol extraction leaves a lipoprotein-free preparation that stimulates TLR4 alone [6 ]. Comparing TLR2- and TLR4-selective stimuli with respect to neutrophil activation has yielded results that are in part contradictory. Kurt-Jones et al. [16 ] found that when neutrophil responses to repurified LPS were compared with commercial LPS, IL-8 production and superoxide generation were substantially reduced. In addition, although both responses were enhanced by GM-CSF priming, commercial LPS showed a greater dose-dependence on GM-CSF, suggesting that GM-CSF preferentially enhanced the TLR2-dependent neutrophil responses [16 ]. Other groups have also shown that selective TLR2 stimuli are potent inducers of neutrophil responses [58 , 59 ]. Work from our group has shown TLR4 expression on neutrophils and that repurified LPS is an extremely potent activator of neutrophils, causing MAPK activation and increased L-selectin shedding, CD11b expression, respiratory burst, and cytokine generation [17 , 20 ]. Similarly, Hayashi and co-workers [15 ] also found that repurified LPS was a potent activator of neutrophils. Activation of neutrophils by LPS is CD14 and LPS-binding protein/serum-dependent [20 , 50 , 59 ], and in keeping with a lesser role for CD14 in TLR2 signaling, lipoproteins (but perhaps not LTAs, see below) activate TLRs in a CD14-independent manner [59 ]. Other candidate activators such as zymosan are complicated particles that activate neutrophils via mechanisms that may include TLRs but also include CD11b/CD18 and autocrine platelet-activating factor generation [60 ]. The ß-glucans are cell wall components of yeasts, fungi, and some bacteria, which possess immunomodulatory activities that enhance resistance to infections [61 ]. Dectin-1 is the major ß-glucan receptor on macrophages [62 ] and mediates their cellular responses to zymosan and live yeast pathogens [63 , 64 ], and there is now evidence that Dectin-1 is also expressed on neutrophils [65 ]. Thus, comparison of the activity of TLR agonists is fraught, as they may activate additional receptors, exhibit complex behavior with respect to dependence on costimulatory molecules, and contain biological contaminants, and finally, it is often extremely difficult or even impossible to calculate molarity or determine receptor pharmacology [24 ].


   TLR-INDUCED NEUTROPHIL SURVIVAL
TOP
 ABSTRACT
 INTRODUCTION
 TOLL-LIKE RECEPTORS (TLRs):...
 TLR-INDUCED NEUTROPHIL...
 TLR-INDUCED NEUTROPHIL SURVIVAL
RECENT UPDATES FROM THE...
 CONCLUDING REMARKS
 REFERENCES
 
Apoptotic cell death is a crucial, injury-limiting mechanism of inflammatory resolution. There is an extensive body of work with respect to LPS activation; however, this needs revisiting in light of data showing differences between selective TLR2 and TLR4 activation and the potential role of monocytes in controlling these effects [17 , 66 , 67 ]. In vitro studies suggest that changes in the local environment produce signals that delay (e.g., LPS [68 , 69 ]) or accelerate (e.g., TNF-related apoptosis-inducing ligand [70 ]; Fas receptor ligation [71 ]) neutrophil apoptosis. The regulation of neutrophil survival mediated by cytokines or other exogenous factors appears to be controlled by activation of transcriptional signaling pathways that involve NF-{kappa}B and the MAPKs, and some signals additionally activate PI-3K [72 73 74 75 76 77 ]. These pathways subsequently control caspase activation [78 79 80 ] with complex downstream effects [81 ] and also regulate the expression of a range of proapoptotic or prosurvival members of the Bcl-2 family. Neutrophils constitutively express proapoptotic proteins (including Bax, Bid, Bak, and Bad) and relatively low levels of expression of antiapoptotic Bcl members (Bcl-xL, A1, and Mcl-1) [82 ]. However, these proteins are highly and transiently expressed when neutrophils are exposed to survival factors [83 , 84 ].

Although the effects of pathogens on neutrophil survival have long been known [69 , 85 ], it is only recently that the effects of selective TLR activation have been studied [17 , 58 , 86 ]. It was recently reported that unmethylated CpG motifs, which are prevalent in bacterial DNA and are recognized by TLR9, markedly enhanced neutrophil viability by delaying spontaneous apoptosis [86 ]; however, the vast majority of work has so far focused on the effects of activation of TLR4 or TLR2 on neutrophil survival. Work by our group found TLR4 to be more effectively coupled to neutrophil survival than TLR2 [17 ], an effect also subsequently observed by Radsak and co-workers [87 ]. Repurified LPS almost completely prevented neutrophil apoptosis at early time-points (4 h) via a mechanism dependent on NF-{kappa}B and MAPK signaling cascades, and in contrast, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteinyl-seryl-(lysyl)(3)-lysine (Pam3CSK4)-induced TLR2 signals showed less efficacy in preventing constitutive apoptosis over short time courses [17 ]. We showed that monocyte contamination of neutrophil cell preparations may be important in apparent, direct responses to LPS. Prolonged neutrophil survival (22 h) was dependent on monocyte-released neutrophil survival factors induced by activation of TLR4 but not TLR2, and indeed, TLR2 activation in monocyte/neutrophil cocultures did not prevent late neutrophil apoptosis [17 , 67 ]. Furthermore, antiapoptotic action of IL-1ß, thought to be involved in neutrophil survival in response to LPS [88 ], is also mediated by peripheral blood mononuclear cell (PBMC) contaminants [66 ], in keeping with the predominant expression of the IL-1RII decoy receptor on neutrophils [89 ]. PBMC-dependent neutrophil survival responses have also been observed with TNF-{alpha} [90 ], and similarly, to our work in neutrophils, LPS-mediated, enhanced survival of eosinophils also requires PBMCs to be present [91 ]. It is interesting that other groups have shown an antiapoptotic effect of TLR2 [58 , 92 ]. Lotz et al. [58 ] reported that the TLR2 agonist LTA inhibited spontaneous neutrophil apoptosis at late time-points (24–72 h), and this was dependent on functional TLR2 and CD14 but not TLR4. One potential reason for the apparently greater efficacy of LTA in inhibiting apoptosis than Pam3CSK4 is the finding that the two agonists have distinct binding domains on the TLR2 molecule [93 ]. In addition, the two agonists may use different heterodimers—studies suggest TLR2/1 mediates responses to Pam3CSK4—and although it still remains to be clarified whether LTA binds to TLR2/1 or TLR2/6, these two heterodimers are known to induce differential cellular responses [94 , 95 ].

Adding a further level of complexity to the story, activation of TLR2 or TLR4 has been shown to be proapoptotic in cell types other than the neutrophil. In endothelial cells, LPS induces apoptosis by a Fas-associated death domain (FADD) protein-dependent pathway [26 , 96 ], and in human embryonic kidney 293 cells, TLR2/6 stimulation by lipoproteins induced apoptotic cell death, which was regulated by MyD88, p38, and FADD [97 98 99 ]. In THP-1 cells, a human monocytic cell line, Pam3CSK4, induces apoptosis through TLR2 [98 ], and in macrophages, pathogenic bacteria have been shown to induce apoptosis through pathways that involve predominantly TLR4 [100 101 102 ]. It is clear that pathogenic bacteria and their products induce apoptosis in host cells through the activation of TLRs, limiting the lifespan of cells and potentially controlling the duration of acute responses to bacteria. Why activation of neutrophils has the opposite effect and appears to prolong their life is still unclear, although it may be to extend the time-frame for these important effector cells to execute their antimicrobial functions. A recent publication reported that neutrophils from patients with tuberculosis show increased, spontaneous apoptosis and accelerated apoptosis in response to Mycobacterium tuberculosis compared with controls [103 ]. This may reflect a delicate balance controlling neutrophil survival, whereby apoptosis is inhibited to allow the cells time to control infection but then accelerated to prevent uncontrolled inflammation.


   RECENT UPDATES FROM THE SOCIETY FOR LEUKOCYTE BIOLOGY’S 37th ANNUAL MEETING
TOP
 ABSTRACT
 INTRODUCTION
 TOLL-LIKE RECEPTORS (TLRs):...
 TLR-INDUCED NEUTROPHIL...
 TLR-INDUCED NEUTROPHIL SURVIVAL
 RECENT UPDATES FROM THE...
CONCLUDING REMARKS
 REFERENCES
 
Lipid rafts are dynamic microdomains with which signal transduction elements associate. In LPS-treated human neutrophils, several cytoskeletal proteins were identified in lipid rafts, suggesting reorganization of the neutrophil plasma membrane may contribute to the cellular phenotype of LPS-activated neutrophils [104 ]. Lipid rafts may also play a role in responses to whole bacteria, as they are recruited to the vicinity of the neutrophil plasma membrane to which the bacteria are attached, and this process may be important for phagosome maturation [105 ]. Jia and co-workers [106 ] suggested a mechanism for LPS-induced survival, in which LPS causes disruption of interactions between caspase-8 and the proapoptotic membrane phosphatase Src homology-containing tyrosine phosphatase-1, which facilitates caspase-8 tyrosine phosphorylation and thus inhibits neutrophil apoptosis. Work from our group [107 ] found that the phenomenon of endotoxin tolerance, characterized by decreased responsiveness of monocytes to LPS following a prior exposure to the same stimulus, also occurs in human neutrophils, resulting in specific alterations in cell function that may represent a reprogramming of cellular function as a means of adaptation to bacterial infection (manuscript in preparation).


   CONCLUDING REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 TOLL-LIKE RECEPTORS (TLRs):...
 TLR-INDUCED NEUTROPHIL...
 TLR-INDUCED NEUTROPHIL SURVIVAL
 RECENT UPDATES FROM THE...
 CONCLUDING REMARKS
REFERENCES
 
Neutrophils play a vital role in host defense to pathogenic infection. It is now clear that TLRs orchestrate these responses, affecting most aspects of the innate-immune system. Although the study of TLRs in the human neutrophil is still in its infancy, there is an expanding body of data demonstrating the vital importance of the TLR in recognizing, and the neutrophil in responding to, the pathogenic world around us. Future studies will continue to improve our understanding of the relationship between neutrophils and TLRs, revealing new approaches to modulate this system and potentially affect disease mechanisms.

Received November 4, 2004; accepted January 15, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 TOLL-LIKE RECEPTORS (TLRs):...
 TLR-INDUCED NEUTROPHIL...
 TLR-INDUCED NEUTROPHIL SURVIVAL
 RECENT UPDATES FROM THE...
 CONCLUDING REMARKS
 REFERENCES
 

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