Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis

Alves-Filho, José C.; Freitas, Aguinaldo de; Souto, Fabrício Oliveira; Spiller, Fernando; Paula-Neto, Heitor A.; Silva, João; Gazzinelli, Ricardo T.; Teixeira, Mauro Martins; Ferreira, Sérgio Henrique; Cunha, Fernando

doi:10.1073/pnas.0900196106

Cited by 220 publications

(260 citation statements)

References 32 publications

(34 reference statements)

Supporting

Mentioning

238

Contrasting

Unclassified

Order By: Relevance

“…Similarly, expression of TLR2, which has been previously demonstrated to regulate neutrophil migration via CXCR2, and surface expression of CXCR2 did not differ between WT and GILZ-KO neutrophils and was not affected by DEX treatment (Fig. 2C) (32).…”

Section: Effect Of Dex On Neutrophil Migration In Gilz-ko Mice With Pmentioning

confidence: 85%

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

et al. 2017

View full text Add to dashboard Cite

The glucocorticoid-induced leucine zipper (GILZ) gene is a pivotal mediator of the anti-inflammatory effects of glucocorticoids (GCs) that are known to regulate the function of both adaptive and innate immunity cells. Our aim was to investigate the role of GILZ in GC-induced inhibition of neutrophil migration, as this role has not been investigated before. We found that GILZ expression was induced by dexamethasone (DEX), a synthetic GC, in neutrophils, and that it regulated migration of these cells into inflamed tissues under DEX treatment. Of note, inhibition of neutrophil migration was not observed in GILZ-knockout mice with peritonitis that were treated by DEX. This was because DEX was unable to up-regulate annexin A1 (Anxa1) expression in the absence of GILZ. Furthermore, we showed that GILZ mediates Anxa1 induction by GCs by transactivating Anxa1 expression at the promoter level via binding with the transcription factor, PU.1. The present findings shed light on the role of GILZ in the mechanism of induction of Anxa1 by GCs. As Anxa1 is an important protein for the resolution of inflammatory response, GILZ may represent a new pharmacologic target for treatment of inflammatory

show abstract

Section: Effect Of Dex On Neutrophil Migration In Gilz-ko Mice With Pmentioning

confidence: 85%

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Paradoxically, LTA has also been shown to be anti-inflammatory in suppressing neutrophil recruitment in response to polymicrobial sepsis through the downregulation of the chemokine receptor CXCR2 on neutrophils [16]. TLR2 À/À animals showed decreased cytokine production, higher bacterial clearance and improved survival.…”

Section: Introductionmentioning

confidence: 99%

“…LTA-induced Weibel-Palade body exocytosis in aortic endothelial cells with release of von Willebrand factor and P-selectin was also enhanced by IFN-g priming [15]. Priming has been attributed to enhanced TLR2 expression [12] or the recruitment of intracellular TLR2 to the cell membrane [13].Paradoxically, LTA has also been shown to be anti-inflammatory in suppressing neutrophil recruitment in response to polymicrobial sepsis through the downregulation of the chemokine receptor CXCR2 on neutrophils [16]. TLR2 À/À animals showed decreased cytokine production, higher bacterial clearance and improved survival.…”

mentioning

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

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

“…They play a crucial role in modulating innate immune-inflammatory response and outcome of sepsis. Disruption or antibody neutralization of specific TLRs including TLR2, TLR3, TLR4, and TLR9 has been shown to improve survival in a polymicrobial mice model of sepsis (6)(7)(8). Further, a recent study has reported cross-talk between TLR4 and TLR2 signaling pathways in augmenting proinflammatory response and mortality in sepsis (9).…”

mentioning

confidence: 99%

Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis

Kong

Thimmulappa

Craciun

et al. 2011

Am J Respir Crit Care Med

188

155

View full text Add to dashboard Cite

Rationale: Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protects against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear. Objectives: To determine whether Nrf2 in myeloid leukocytes alters inflammatory response and protects against sepsis. Methods: Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced sepsis and were assessed for survival, organ injury, systemic inflammation, and bacteremia. Using LPS-stimulated peritoneal macrophages, Toll-like receptor (TLR) 4 surface trafficking and downstream signaling events were analyzed. Measurements and Main Results: Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1 2/2 compared with respective floxed controls (Keap1 f/f or Nrf2 f/f ) and significantly elevated in LysM-Nrf2 2/2 mice after cecal ligation and puncture. Peritoneal macrophages from septic LysM-Keap1 2/2 mice showed a greater bacterial phagocytic activity compared with LysM-Nrf2 2/2 and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2 2/2 compared with LysM-Keap1 2/2 mice and floxed controls. Conclusions: Our study shows that Nrf2 acts as a critical immunomodulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.

show abstract

Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis

Cited by 220 publications

References 32 publications

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

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

Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis

Contact Info

Product

Resources

About