TLR4 signaling is essential for survival in acute lung injury induced by virulent Pseudomonas aeruginosa secreting type III secretory toxins

Faure, Karine; Sawa, Teiji; Ajayi, Temitayo; Fujimoto, Junichi; Moriyama, Kiyoshi; Shime, Nobuaki; Wiener-Kronish, Jeanine P.

doi:10.1186/1465-9921-5-1

Cited by 74 publications

(65 citation statements)

References 38 publications

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“…In vitro, bone marrow cells lacking TLR4 exhibited blunted TNF-␣ expression when stimulated with P. aeruginosa. In vivo, the cytokine and inflammatory responses to pulmonary infection with P. aeruginosa were significantly impaired in TLR4 Ϫ/Ϫ mice compared with wild-type controls, consistent with recent observations in mice with nonfunctional mutations in TLR4 (14,44). Ramphal et al (46) similarly found reduced cytokine responses in TLR4…”

Section: Discussionsupporting

confidence: 76%

Redundant Toll-like receptor signaling in the pulmonary host response toPseudomonas aeruginosa

Skerrett

Wilson

Liggitt

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

128

127

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Activation of pulmonary defenses against Pseudomonas aeruginosa requires myeloid differentiation factor 88 (MyD88), an adaptor for Toll-like receptor (TLR) signaling. To determine which TLRs mediate recognition of P. aeruginosa, we measured cytokine responses of bone marrow cells from wild-type mice and mice lacking TLR2 (TLR2−/−), TLR4 (TLR4−/−), TLR2 and TLR4 (TLR2/4−/−), or MyD88 (MyD88−/−) to wild-type P. aeruginosa and to fliC P. aeruginosa, which lacks the TLR5 ligand flagellin. Mice also were challenged with aerosolized bacteria to determine cytokine responses, lung inflammation, and bacterial clearance. TNF induction required MyD88 and was absent in TLR2/4−/−cells in response to fliC but not wild-type P. aeruginosa, whereas TLR2−/−cells exhibited augmented responses. In vivo, TLR4−/−mice responded to wild-type P. aeruginosa with reduced cytokine production and inflammation, but intact bacterial clearance, while TLR2−/−mice had partially impaired cytokine responses and delayed bacterial killing despite normal inflammation. When challenged with fliC, MyD88−/−mice failed to mount early cytokine and inflammatory responses or control bacterial replication, resulting in necrotizing lung injury and lethal disseminated infection. TLR4−/−and TLR2/4−/−mice responded to fliC infection with severely limited inflammatory and cytokine responses but intact bacterial clearance. TLR2−/−mice had partially reduced cytokine responses but augmented inflammation and preserved bacterial killing. These data indicate that TLR4- and flagellin-induced signals mediate most of the acute inflammatory response to Pseudomonas and that TLR2 has a counterregulatory role. However, MyD88-dependent pathways, in addition to those downstream of TLR2, TLR4, and TLR5, are required for pulmonary defense against P. aeruginosa.

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Section: Discussionsupporting

confidence: 76%

Redundant Toll-like receptor signaling in the pulmonary host response toPseudomonas aeruginosa

Skerrett

Wilson

Liggitt

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

128

127

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“…Morphologic changes in the C3H/HeJ mice were not demonstrable during the first week of life, and the subsequent changes were coincident with bacterial colonization and inflammation. Although TLR4 signaling is essential for clearance of GNB in experimental models of pneumonia in adult mice (18,19,24), the present study demonstrates a potential role for TLR4 in preventing bacterial colonization in the developing lung of the C3H strain. In the cage system of our vivarium, immature mice are exposed to various bacteria in the litter and their excreta, but the absence of TLR4 signaling results in a significantly greater transient bacterial colonization of lungs in the C3H/HeJ strain compared with controls.…”

Section: Discussionmentioning

confidence: 97%

“…Toll-like receptor 4 (TLR4) serves as a PRR for GNB by recognizing lipopolysaccharide (LPS) (16) and mediating LPS responsiveness (17). Studies in adult mice lacking TLR4 signaling have shown that this receptor is essential for clearance of GNB (18,19). C3H/HeJ mice have a naturally occurring missense mutation in the cytoplasmic domain of TLR4 abolishing responsiveness to LPS (17).…”

mentioning

confidence: 99%

Altered Postnatal Lung Development in C3H/HeJ Mice

et al. 2006

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C3H/HeJ mice develop an increase in terminal air space area detectable by postnatal d 14 that persists into adulthood compared with strain-matched controls (C3H/SnJ, C3H/OuJ). Morphometric quantification revealed a 50% increase in terminal air space area by postnatal d 14 and a 2.3-fold increase by 2 mo of age in C3H/HeJ mice. Bacteriologic cultures obtained from the left lung on postnatal d 7 revealed Ͼ100 colony-forming units (CFU)/left lung of predominantly Gram-negative bacteria (GNB) (Escherichia coli and Proteus mirabilis) in 13 of the 14 C3H/HeJ mice compared with 0 of 12 controls demonstrating colonization of the developing lung in C3H/HeJ mice. An approximately threefold increase in macrophages from bronchoalveolar lavage, threefold increases in matrix metalloproteinase 12 (MMP-12) mRNA and protein levels and elevated levels of proinflammatory cytokines monocyte chemoattractant protein (MCP-1) and keratinocyte-derived cytokine (KC) were also found. B ronchopulmonary dysplasia (BPD) is an important cause of morbidity and mortality in preterm infants, affecting 40% of all infants born with a birth weight Ͻ1000 g (1). The routine use of antenatal steroids, surfactant, and gentler ventilation strategies has led to the emergence of the "new" BPD, which predominantly affects extremely low birth weight infants (2,3) who despite requiring minimal or no ventilatory support still progress to BPD (3,4). Lung pathology in these infants reveals large, simplified alveolar structures and abnormalities in microvasculature development with variable interstitial cellularity (5). Although BPD is a multifaceted disease, lung infections have been implicated in the pathogenesis of BPD (6,7). Ureaplasma urealyticum, Gram-positive bacteria, and GNB frequently colonize lungs of the premature infant and have been associated with BPD (6 -9). The underlying mechanisms by which bacterial colonization of the immature lung can result in morphologic changes seen in BPD have not been elucidated.Mice are born with lungs in the saccular phase of development; alveolarization is initiated around postnatal d 5 and is completed in the first 2-3 wk of life (10). Because lung development in mice parallels that in preterm infants who are born with their lungs in late canalicular or early saccular phase (11), mice can serve as a model of the developing premature human lung. It is well established that the preterm infant is at increased risk of infections because various components of the immune system are not well developed (12,13). Decreased expression of innate host defense molecules might alter susceptibility to bacterial colonization and chronic inflammation leading to morphologic changes in the lung architecture characteristic of BPD.Mammalian Toll-like receptors are pattern recognition receptors (PRRs) that interact with pathogen-associated molecular patterns and serve as the recognition and effector arm of the innate immune response (14,15). Toll-like receptor 4 (TLR4) serves as a PRR for GNB by recognizing lipopolysaccharide (L...

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“…Inflammation, tissue damage, and lethality are diminished in the absence of TLR4 signaling (29). However, in the setting of infection with live bacteria, the contribution of TLR4 varies depending on the experimental model and type of organism used in the study (13)(14)(15)(30)(31)(32)(33)(34)(35)(36)(37). Most early studies used mouse strains with mutant forms of TLR4.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

Deng

Scott

Loughran

et al. 2013

The Journal of Immunology

171

137

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The morbidity associated with bacterial sepsis is the result of host immune responses to pathogens, which are dependent on pathogen recognition by pattern recognition receptors, such as TLR4. TLR4 is expressed on a range of cell types, yet the mechanisms by which cell-specific functions of TLR4 lead to an integrated sepsis response are poorly understood. To address this, we generated mice in which TLR4 was specifically deleted from myeloid cells (LysMTLR4KO) or hepatocytes (HCTLR4KO) and then determined survival, bacterial counts, host inflammatory responses, and organ injury in a model of cecal ligation and puncture (CLP), with or without antibiotics. LysM-TLR4 was required for phagocytosis and efficient bacterial clearance in the absence of antibiotics. Survival, the magnitude of the systemic and local inflammatory responses, and liver damage were associated with bacterial levels. HCTLR4 was required for efficient LPS clearance from the circulation, and deletion of HCTLR4 was associated with enhanced macrophage phagocytosis, lower bacterial levels, and improved survival in CLP without antibiotics. Antibiotic administration during CLP revealed an important role for hepatocyte LPS clearance in limiting sepsis-induced inflammation and organ injury. Our work defines cell type–selective roles for TLR4 in coordinating complex immune responses to bacterial sepsis and suggests that future strategies for modulating microbial molecule recognition should account for varying roles of pattern recognition receptors in multiple cell populations.

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TLR4 signaling is essential for survival in acute lung injury induced by virulent Pseudomonas aeruginosa secreting type III secretory toxins

Cited by 74 publications

References 38 publications

Redundant Toll-like receptor signaling in the pulmonary host response toPseudomonas aeruginosa

Redundant Toll-like receptor signaling in the pulmonary host response toPseudomonas aeruginosa

Altered Postnatal Lung Development in C3H/HeJ Mice

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

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