Integration of Toll-like receptor and phagocytic signaling for tailored immunity

Underhill, David; Gantner, Benjamin N.

doi:10.1016/j.micinf.2004.08.016

Cited by 132 publications

(113 citation statements)

References 31 publications

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“…Collectively, these findings suggest that MyD88-independent mechanisms are responsible for controlling bacterial replication in the CNS parenchyma. Indeed, because TLRs and the IL-1 and IL-18 receptors are not phagocytic receptors, it may be expected that alternative phagocytic pattern recognition receptors are responsible for pathogen uptake and neutralization (65,66). Some candidate receptors that may participate in regulating S. aureus burdens in the CNS parenchyma include members of the scavenger receptor family as well as opsonic receptors including Fc and complement receptors (67,68).…”

Section: Discussionmentioning

confidence: 99%

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

Kielian

Phulwani

Esen

et al. 2007

The Journal of Immunology

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Brain abscesses form in response to a parenchymal infection by pyogenic bacteria, with Staphylococcus aureus representing a common etiologic agent of human disease. Numerous receptors that participate in immune responses to bacteria, including the majority of TLRs, the IL-1R, and the IL-18R, use a common adaptor molecule, MyD88, for transducing activation signals leading to proinflammatory mediator expression and immune effector functions. To delineate the importance of MyD88-dependent signals in brain abscesses, we compared disease pathogenesis using MyD88 knockout (KO) and wild-type (WT) mice. Mortality rates were significantly higher in MyD88 KO mice, which correlated with a significant reduction in the expression of several proinflammatory mediators, including but not limited to IL-1β, TNF-α, and MIP-2/CXCL2. These changes were associated with a significant reduction in neutrophil and macrophage recruitment into brain abscesses of MyD88 KO animals. In addition, microglia, macrophages, and neutrophils isolated from the brain abscesses of MyD88 KO mice produced significantly less TNF-α, IL-6, MIP-1α/CCL3, and IFN-γ-induced protein 10/CXCL10 compared with WT cells. The lack of MyD88-dependent signals had a dramatic effect on the extent of tissue injury, with significantly larger brain abscesses typified by exaggerated edema and necrosis in MyD88 KO animals. Interestingly, despite these striking changes in MyD88 KO mice, bacterial burdens did not significantly differ between the two strains at the early time points examined. Collectively, these findings indicate that MyD88 plays an essential role in establishing a protective CNS host response during the early stages of brain abscess development, whereas MyD88-independent pathway(s) are responsible for pathogen containment.

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Section: Discussionmentioning

confidence: 99%

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

Kielian

Phulwani

Esen

et al. 2007

The Journal of Immunology

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“…Indeed, recent evidence has revealed the existence of receptor cross-talk between TLRs and phagocytic receptors (Underhill and Gantner, 2004;Underhill and Ozinsky, 2002). For example, recent studies suggest that TLRs may regulate phagosome formation and maturation as well as modulate the transcription of some phagocytic receptors, while signaling via phagocytic receptors can also modulate TLR signaling (Underhill and Gantner, 2004). Relevant to the current study, through its ability to enhance TLR-dependent signaling, CD14 may also influence microglial activation by regulating the expression and/or activity of phagocytic PRRs.…”

Section: Discussionmentioning

confidence: 99%

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

Esen

Kielian

2005

Journal of Neuroimmunology

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Recognition of Staphylococcus aureus and its cell-wall component peptidoglycan (PGN) by microglia is mediated, in part, by Toll-like receptor 2 (TLR2). However, the pattern recognition receptor (PRR) CD14 can also bind PGN and enhance TLR2-mediated signaling in macrophages, suggesting a similar phenomenon might occur in microglia. To assess the functional significance of CD14 on microglial activation, we evaluated the responses of primary microglia isolated from CD14 knockout (KO) and wild type (WT) mice. PGN-dependent microglial activation was partially CD14-dependent as demonstrated by the attenuated expression of TNF-α, macrophage inflammatory protein-2 (MIP-2/CXCL2), and the soluble PRR pentraxin-3 in CD14 KO microglia compared to WT cells. In contrast, microglial responses to intact S. aureus occurred primarily via a CD14-independent manner. Collectively, these findings reveal the complex nature of gram-positive bacterial recognition by microglia, which occurs, in part, via CD14.

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“…Engagement of these receptors activates a series of intracellular signaling pathways that lead to dynamic and rapid cytoskeletal rearrangements as well as membrane trafficking required for macrophage phagocytosis (3)(4)(5). In addition to the aforementioned receptors, microbial internalization is usually accompanied by activation of Toll-like receptors (TLRs) that recognize unique pathogen-associated molecular patterns shared by large groups of pathogens (6), indicating that TLR activation and phagocytosis are functionally linked (7).…”

mentioning

confidence: 99%

Eps8 Protein Facilitates Phagocytosis by Increasing TLR4-MyD88 Protein Interaction in Lipopolysaccharide-stimulated Macrophages

Chen

Hsieh

Chang

et al. 2012

Journal of Biological Chemistry

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Background: TLR4-mediated p38 MAPK and actin cytoskeleton reorganization are important for macrophage phagocytosis. Results: TLR4-induced Eps8 facilitates TLR4-MyD88 interaction, leading to the activation of p38 MAPK, actin polymerization, and the uptake of bacteria in macrophages. Conclusion: Eps8 is critical in innate immunity. Significance: This is the first report to indicate that Eps8 contributes to efficient phagocytosis in macrophages.

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Integration of Toll-like receptor and phagocytic signaling for tailored immunity

Cited by 132 publications

References 31 publications

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

Eps8 Protein Facilitates Phagocytosis by Increasing TLR4-MyD88 Protein Interaction in Lipopolysaccharide-stimulated Macrophages

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