A TLR2 ligand suppresses inflammation by modulation of chemokine receptors and redirection of leukocyte migration

McKimmie, Clive S.; Moore, Mark; Fraser, Alasdair R.; Jamieson, Thomas; Xu, Damo; Burt, Claire L.; Pitman, Nick; Nibbs, Robert J. B.; McInnes, Iain B.; Liew, Foo Y.; Graham, Gerard J.

doi:10.1182/blood-2008-08-174698

Cited by 27 publications

(24 citation statements)

References 42 publications

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“…TLR2 À/À animals showed decreased cytokine production, higher bacterial clearance and improved survival. A similar inhibitory effect was seen with bacterial lipoproteins from Gram-positive organisms in a model of cutaneous infection, leading to re-routing of neutrophils from sites of imflammation to secondary lymphoid organs [17]. More recently, a ''PGN-embedded molecule'' that is TLR2-and TLR6-dependent was shown to inhibit IL-2 production by T cells in response to S. aureus superantigens through the induction of IL10 and apoptosis of antigen presenting cells [18].…”

Section: Introductionmentioning

confidence: 71%

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

et al. 2010

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The response of leukocytes to lipoteichoic acid (LTA), a TLR2-dependent major cell wall component of Staphylococcus aureus, is linked to the outcome of an infection. In this study we investigated the role of nonhematopoietic TLR2 in response to LTA and S. aureus by creating bone marrow chimeras. Significant leukocyte recruitment in response to LTA required IFN-c priming in WT C57BL/6 and TLR2 À/À ) WT mice, but was not observed in TLR2 À/À or WT ) TLR2 À/À animals. LTA also induced a proinflammatory response in IFN-c primed primary human microvascular endothelial cells leading to leukocyte recruitment in vitro. When mice were infected with S. aureus, the most profound elevation of TNF-a and IL-6 was seen in TLR2 À/À and TLR2 À/À ) WT mice. TLR2 À/À , but not chimeric mice, demonstrated increased IL-17, blood leukocytosis and pulmonary neutrophilia compared to WT mice. Collectively, the results suggest an essential role for IFN-c and nonhematopoietic TLR2 for leukocyte recruitment in response to LTA. In contrast, TLR2 on both hematopoietic and nonhematopoietic cells appears to orchestrate an inhibitory response to S. aureus such that in complete TLR2 deficiency, there is an exaggerated proinflammatory response and/or skewing of the immune response towards a Th17 phenotype that may contribute to the decreased survival of TLR2 À/À mice. Key words: Endothelial cells . Leukocyte recruitment . Lipoteichoic acidStaphyloccoccus aureus . TLR2 IntroductionStaphyloccoccus aureus is the most common causative agent of bacteremia in the Western world and is associated with high mortality. Despite the increasing importance of S. aureus infection, how the pathogen is recognized by the innate immune system in vivo remains incompletely understood. S. aureus possesses a number of PAMP that may activate the host innate immune system [1]. These PAMP include peptidoglycan (PGN), lipoteichoic acid (LTA), lipoproteins and unmethylated CpG DNA. PGN is recognized by the peptidoglyan recognizing proteins and the PGN subcomponent muramyl dipeptide (MDP) is recognized by the cytosolic sensor nucleotide-binding oligomerization domain 2 (NOD2). S. aureus LTA and lipoproteins are recognized by TLR2. CpG DNA is recognized by TLR9. The strongest evidence to date suggests that both TLR2 and NOD, Eur. J. Immunol. 2010. 40: 1639-1650 DOI 10.1002 Immunity to infection 1639 possibly in concert, facilitate innate immune recognition of S. aureus [2][3][4][5]. However the in vivo importance of each PAMP from S. aureus in driving the innate immune response and the target cells each acts on has not been clearly elucidated. The important role of TLR2 in host defense against S. aureus has long been established. An intravenous inoculum of 10 7 organisms resulted in 90% mortality by day 14 in TLR2-deficient mice, compared to 40% in WT animals [2]. A larger inoculum (10 8 cfu) resulted in 100% mortality by day 5 [3]. Mortality in TLR2 À/À mice was correlated with the inhibition of TNF-a production by peritoneal macrophages in response to LTA, a major cell wal...

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Section: Introductionmentioning

confidence: 71%

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

et al. 2010

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Section: Discussionmentioning

confidence: 99%

“…The down-regulation of chemokine receptor function on inflammatory cells by TLR agonists occurs in two manners: a slower (in hours) process with reduction of gene expression and mRNA stability associated with cell differentiation and a rapid (within minutes) interference in receptors function resembling "desensitization" (34,35). For example, the TLR2 ligand Pam3CSK4 suppresses the migration of mouse monocytes by down-regulating CCR1, CCR2, and CCR5 genes, whereas another TLR2 ligand lipoteichoic acid interferes with the chemotaxis of mouse neutrophils by inhibiting the function of another chemokine receptor CXCR2 (33,36,37). Our study showed that CCR2 on Ly6C ϩ immature inflammatory DCs was rapidly down-regulated after LPS stimulation for 1 h with increased function of Fpr2.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that TLR2 activation by lipoteichoic acid from Staphylococcus aureus inhibits CCR1, CCR2, and CCR5 function on human monocytic cells and thus inhibits cell migration in response to chemokine agonists (10,33). This down-regulation of the expression pattern of chemokine receptors by TLRs is important to retain infiltrating cells at sites of infection (10,33). The down-regulation of chemokine receptor function on inflammatory cells by TLR agonists occurs in two manners: a slower (in hours) process with reduction of gene expression and mRNA stability associated with cell differentiation and a rapid (within minutes) interference in receptors function resembling "desensitization" (34,35).…”

Section: Discussionmentioning

confidence: 99%

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Signal Relay by CC Chemokine Receptor 2 (CCR2) and Formylpeptide Receptor 2 (Fpr2) in the Recruitment of Monocyte-derived Dendritic Cells in Allergic Airway Inflammation

Chen

Liu

et al. 2013

Journal of Biological Chemistry

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“…28 CFSE and TAMRA-stained cells were washed, mixed 1:1, and injected subcutaneously into TPA-inflamed skin. After 24 hours, inguinal LNs were removed and 8-mm skin biopsies taken, frozen, and 8-m sections cut for immunostaining.…”

Section: Adoptive Transfer Of Labeled Dcs To Inflamed Skinmentioning

confidence: 99%

D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion

Lee

McKimmie

Gilchrist

et al. 2011

Blood

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IntroductionLymphatic endothelium plays essential roles in regulating fluid and chemokine-dependent antigen-presenting cell (APC) movement from peripheral sites to draining lymph nodes (LNs). 1 The chemokine family 2 is functionally subdivided into inflammatory and constitutive subsets. 3 Inflammatory chemokines are involved in recruiting leukocytes to sites of infection or damage, whereas constitutive chemokines are involved in more precise, tissuespecific, trafficking, including movement into secondary lymphoid organs as part of the adaptive immune response. Initiation of adaptive immune responses requires selective migration of APCs expressing the constitutive chemokine receptor, CCR7, to LNs. 4 To facilitate this, lymphatic endothelium selectively expresses, and presents, the CCR7 ligands CCL19 and CCL21. However, in the context of inflamed peripheral tissues, in which inflammatory chemokines will be abundant, it is unclear how selective presentation of constitutive chemokines by lymphatic endothelium is achieved.In addition to the family of signaling chemokine receptors, we and others have been studying a subfamily of atypical chemokine receptors characterized by an apparent inability to signal after ligand binding. 5,6 Further studies have shown some of these receptors to be active as chemokine-scavenging receptors, implicating them in negative regulation of chemokine-driven processes. [7][8][9] We are particularly interested in the D6 chemokine-scavenging receptor. 10 This molecule scavenges by binding inflammatory CC-chemokines with high affinity, internalizing them, and targeting them for intracellular degradation. D6 does not bind, or alter cellular responses to, constitutive CC-chemokines, such as CCL19 or CCL21, or chemokines belonging to any other subfamily and is therefore specific for inflammatory CC-chemokines. 5,[10][11][12] In D6-deficient mice, exaggerated inflammatory responses have been observed, in all tissues in which D6 is normally expressed, 5,[13][14][15][16][17][18] indicating its importance for resolution of in vivo inflammatory responses. However, the major site of D6 expression in vivo is on lymphatic endothelial cells (LECs), 19 and it is difficult to argue for a major role for these cells in inflammatory chemokine scavenging. 20 In addition, D6 is expressed on some leukocyte subtypes, 17,21 including macrophages 19 but predominantly on B cells and dendritic cells (DCs), which are not cells that are typically attracted to, and able to scavenge chemokines at, the epicenter of inflammatory responses. Thus, the cellular basis for in vivo D6 function is currently unclear. In particular, the roles for D6 on LECs have remained elusive.Here we have focused specifically on roles for D6 on lymphatic endothelium and its importance for fluid and cellular trafficking from peripheral tissues to LNs. We report that D6 plays an essential function in regulating lymph flow and cellular efflux from inflamed peripheral sites to draining LNs. D6 achieves this role by preventing The online version of t...

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A TLR2 ligand suppresses inflammation by modulation of chemokine receptors and redirection of leukocyte migration

Cited by 27 publications

References 42 publications

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

Signal Relay by CC Chemokine Receptor 2 (CCR2) and Formylpeptide Receptor 2 (Fpr2) in the Recruitment of Monocyte-derived Dendritic Cells in Allergic Airway Inflammation

D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion

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