NOD2 contributes to cutaneous defense against<i>Staphylococcus aureus</i>through α-toxin-dependent innate immune activation

Hrúz, Petr; Zinkernagel, Annelies S.; Jeníková, Gabriela; Botwin, Gregory J.; Hugot, Jean‐Pierre; Karin, Michael; Nizet, Victor; Eckmann, Lars

doi:10.1073/pnas.0904958106

Cited by 176 publications

(199 citation statements)

References 39 publications

(36 reference statements)

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…To determine whether IFN-g priming was a unique requirement for the response to LTA, HDMEC were stimulated with the triacylated ligand Pam 3 Cys-Ser-(Lys) 4 .trihydrochloride (Pam 3 CSK 4 ) that is recognized by the TLR2/1 heterodimer. IFN-g priming significantly increased IL-6 production in response to Pam 3 CSK 4 in a dose-dependent manner (Fig.…”

Section: Lta Activation Of Human Primary Microvascular Endothelial Cementioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2010

View full text Add to dashboard Cite

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...

show abstract

Section: Lta Activation Of Human Primary Microvascular Endothelial Cementioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Their function in innate immune responses has been extensively studied, revealing pivotal roles in host defense against pathogens such as Listeria monocytogenes, Helicobacter pylori and Staphylococcus aureus [4][5][6] . In humans, deregulated NOD signalling due to mutations in NOD receptors, particularly in NOD2, are associated with Crohn's disease, an inflammatory gastrointestinal disorder [7][8][9] .…”

mentioning

confidence: 99%

A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production

et al. 2015

View full text Add to dashboard Cite

Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-kB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-kB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-kB activation downstream of NOD engagement. Despite only delaying NF-kB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.

show abstract

“…3,[9][10][11] It has also been noted that the elimination of the bacteria can relieve the symptoms in AD patients. 4,5 However, the pathological mechanism underlying S. aureus-exacerbated AD remains to be addressed, and no publications have elucidated the cellular and molecular pathways by which epicutaneous S. aureus infection leads to the deterioration of AD.…”

Section: Discussionmentioning

confidence: 99%

“…NOD2, but not NOD1, was shown to be crucial for the recognition of S. aureus and the induction of antibacterial immunity in a mouse model of skin infection. 9 TLR2 expressed in the skin recognizes S. aureusderived PGN and LTA and induces innate immune responses via intracellular signal transduction. 10,11 TLR2-deficient mice are highly susceptible to S. aureus invasion, and macrophages from these mice release less interleukin (IL)-6 and IL-10 in response to heat-killed S. aureus.…”

Section: Introductionmentioning

confidence: 99%

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

et al. 2015

View full text Add to dashboard Cite

The skin of patients with atopic dermatitis (AD) has a unique predisposition for colonization by Staphylococcus aureus (S. aureus), which contributes to the inflammation and grim prognosis of AD. Although the mechanism underlying the S. aureus-induced exacerbation of AD remains unclear, recent studies have found a pivotal role for pattern recognition receptors in regulating the inflammatory responses in S. aureus infection. In the present study, we used a typical mouse model of AD-like skin inflammation and found that S. aureus-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor 2 (TLR2) ligands exacerbated AD-like symptoms, which were further deteriorated by the in vivo expansion of basophils and eosinophils. Subsequent histological analyses revealed that dermal fibroblasts were pervasive in the AD-like skin lesions. Co-culture of human dermal fibroblasts with basophils and eosinophils resulted in a vigorous cytokine/chemokine response to the NOD2/TLR2 ligands and the enhanced expression of intercellular adhesion molecule-1 on the dermal fibroblasts. Basophils and eosinophils were primarily responsible for the AD-related cytokine/chemokine expression in the co-cultures. Direct intercellular contact was necessary for the crosstalk between basophils and dermal fibroblasts, while soluble mediators were sufficient to mediate the eosinophil-fibroblast interactions. Moreover, the intracellular p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor-kappa B signaling pathways were essential for NOD2/TLR2 ligand-mediated activation of basophils, eosinophils, and dermal fibroblasts in AD-related inflammation. This study provides the evidence of NOD2/TLR2-mediated exacerbation of AD through activation of innate immune cells and therefore sheds light on a novel mechanistic pathway by which S. aureus contributes to the pathophysiology of AD. Cellular & Molecular Immunology

show abstract

NOD2 contributes to cutaneous defense againstStaphylococcus aureusthrough α-toxin-dependent innate immune activation

Cited by 176 publications

References 39 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

A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

Contact Info

Product

Resources

About