Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection

Andonegui, Graciela; Zhou, Hong; Bullard, Daniel C.; Kelly, Margaret M.; Mullaly, Sarah C.; McDonald, Braedon; Long, Elizabeth M.; Robbins, Stephen M.; Kubes, Paul

doi:10.1172/jci36411

Cited by 112 publications

(120 citation statements)

References 46 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

Section: Role Of Tlr2 In Systemic Infection With S Aureusmentioning

confidence: 99%

“…Blood was collected by cardiac puncture for leukocyte count and plasma cytokines. The lung, liver, spleen and kidneys were harvested, weighed and snap frozen in liquid nitrogen for MPO determination [20]. Homogenates of the organs were also prepared in sterile PBS and serial dilutions were plated on LB agar supplemented with 30 mg/mL of kanamycin for cfu determination.…”

Section: S Aureus Infectionmentioning

confidence: 99%

“…There is increasing recognition that endothelial cells are a critical component of the innate immune response to pathogens [19][20][21]. Studies of chimeric [19] and conditional knockout mice [20] have clearly demonstrated that leukocyte recruitment to the lung in response to systemic administration of LPS or Gram-negative sepsis are dependent on TLR4 expressed by endothelium and not leukocytes. Similarly, blockade of endothelial specific NF-kB in transgenic mice, and hence decreased endothelial proinflammatory response, alleviated multiple organ injury and increased the survival of septic mice without affecting the clearance of L. monocytogenes, S. pneumonia and S. enterica [21].…”

Section: Introductionmentioning

confidence: 99%

“…The emphasis of studies so far has been on the interaction of LTA with TLR2 expressed on leukocytes, while relatively less is known about the interaction of LTA with TLR2 on other cell types. There is increasing recognition that endothelial cells are a critical component of the innate immune response to pathogens [19][20][21]. Studies of chimeric [19] and conditional knockout mice [20] have clearly demonstrated that leukocyte recruitment to the lung in response to systemic administration of LPS or Gram-negative sepsis are dependent on TLR4 expressed by endothelium and not leukocytes.…”

mentioning

confidence: 99%

“…Mice were euthanized 20 h later. Blood and organs were harvested for peripheral leukocyte count, myeloperoxidase (MPO) measurement, bacterial colony count and cytokine determination using standard techniques [20].Compared to uninfected controls, there was a profound drop in the number of circulating leukocytes in all four groups of mice upon infection (Fig. 7A).…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2010

Self Cite

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: Role Of Tlr2 In Systemic Infection With S Aureusmentioning

confidence: 99%

Section: S Aureus Infectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

Zhang

Qiu

et al. 2021

Advanced Science

View full text Add to dashboard Cite

IRF8 is a key regulator of innate immunity receptor signaling and plays diverse functions in the development of hematopoietic cells. The effects of IRF8 on hematopoietic stem cells (HSCs) are still unknown. Here, it is demonstrated that IRF8 deficiency results in a decreased number of long-term HSCs (LT-HSCs) in mice. However, the repopulation capacity of individual HSCs is significantly increased. Transcriptomic analysis shows that IFN-and IFNsignaling is downregulated in IRF8-deficient HSCs, while their response to proinflammatory cytokines is unchanged ex vivo. Further tests show that Irf8 −/− HSCs can not respond to CpG, an agonist of Toll-like receptor 9 (TLR9) in mice, while long-term CpG stimulation increases wild-type HSC abundance and decreases their bone marrow colony-forming capacity. Mechanistically, as the primary producer of proinflammatory cytokines in response to CpG stimulation, dendritic cells has a blocked TLR9 signaling due to developmental defect in Irf8 −/− mice. Macrophages remain functionally intact but severely reduce in Irf8 −/− mice. In NK cells, IRF8 directly regulates the expression of Tlr9 and its deficiency leads to no increased IFN production upon CpG stimulation. These results indicate that IRF8 regulates HSCs, at least in part, through controlling TLR9 signaling in diverse innate immune cells.

show abstract

Innate immune system favors emergency monopoiesis at the expense of DC‐differentiation to control systemic bacterial infection in mice

et al. 2015

View full text Add to dashboard Cite

DCs are professional APCs playing a crucial role in the initiation of T-cell responses to combat infection. However, systemic bacterial infection with various pathogens leads to DC-depletion in humans and mice. The mechanisms of pathogen-induced DC-depletion remain poorly understood. Previously, we showed that mice infected with Yersinia enterocolitica (Ye) had impaired de novo DC-development, one reason for DC-depletion. Here, we extend these studies to gain insight into the molecular mechanisms of DC-depletion and the impact of different bacteria on DC-development. We show that the number of bone marrow (BM) hematopoietic progenitors committed to the DC lineage is reduced following systemic infection with different Gram-positive and Gram-negative bacteria. This is associated with a TLR4-and IFN-γ−signaling dependent increase of committed monocyte progenitors in the BM and mature monocytes in the spleen upon Ye-infection. Adoptive

show abstract

Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection

Cited by 112 publications

References 46 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

IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

Innate immune system favors emergency monopoiesis at the expense of DC‐differentiation to control systemic bacterial infection in mice

Contact Info

Product

Resources

About