CD14 Impairs Host Defense against Gram‐Negative Sepsis Caused by<i>Burkholderia pseudomallei</i>in Mice

Wiersinga, W. Joost; Vos, Alex F. de; Wieland, Catharina W.; Leendertse, Masja; Roelofs, Joris J. T. H.; Poll, Tom van der

doi:10.1086/592220

Cited by 33 publications

(37 citation statements)

References 51 publications

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“…Ϫ/Ϫ mice infected intranasally with Streptococcus pneumoniae or Burkholderia pseudomallei exhibited accelerated bacterial killing compared with control mice (26,27). Further, brains of S. pneumoniae-infected CD14 Ϫ/Ϫ mice produced elevated CXCL2/MIP-2, resulting in increased neutrophil infiltration and more severe disease (28), which is similar to our findings with P. aeruginosa-infected corneas.…”

Section: Discussionsupporting

confidence: 87%

CD14 Mediates Toll-like Receptor 4 (TLR4) Endocytosis and Spleen Tyrosine Kinase (Syk) and Interferon Regulatory Transcription Factor 3 (IRF3) Activation in Epithelial Cells and Impairs Neutrophil Infiltration and Pseudomonas aeruginosa Killing in Vivo

Roy¹,

Karmakar

Pearlman

2014

Journal of Biological Chemistry

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Background:The role of CD14 on TLR4 signaling in epithelial cells is not well understood. Results: Blockade of CD14 inhibits TLR4 internalization and IRF3 signaling in human epithelial cells. Conclusion: CD14 regulates TLR4 internalization and signaling in corneal epithelial cells and limits the severity of Pseudomonas aeruginosa corneal infection. Significance: These data provide increased understanding of CD14 and TLR4 signaling in epithelial cells.

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Section: Discussionsupporting

confidence: 87%

CD14 Mediates Toll-like Receptor 4 (TLR4) Endocytosis and Spleen Tyrosine Kinase (Syk) and Interferon Regulatory Transcription Factor 3 (IRF3) Activation in Epithelial Cells and Impairs Neutrophil Infiltration and Pseudomonas aeruginosa Killing in Vivo

Roy¹,

Karmakar

Pearlman

2014

Journal of Biological Chemistry

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“…It remains unclear why neutrophils become sequestered within the liver microvasculature during sepsis/endotoxemia, but it has been hypothesized that hepatic neutrophil sequestration represents a coordinated effort by the host to enhance the clearance of circulating bacteria (20,27). Previous studies have demonstrated enhanced bacterial clearance in CD14 2/2 mice during Gramnegative sepsis (9,26). In our present study, we found that CD14 2/2 mice were able to trap circulating bacteria in the liver as effectively as WT mice.…”

Section: Discussionsupporting

confidence: 55%

The Role of CD14 in Neutrophil Recruitment within the Liver Microcirculation during Endotoxemia

McAvoy

McDonald

Parsons

et al. 2011

The Journal of Immunology

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During Gram-negative sepsis and endotoxemia, CD14 is essential for the recognition of LPS by the TLR4 complex and subsequent generation of systemic inflammation. However, CD14-independent responses to LPS have been reported in vitro and in vivo in selected tissues including the skin. As the liver is a key target organ for neutrophil sequestration and inflammatory pathology during sepsis and endotoxemia, we investigated the role of CD14 in the recruitment of neutrophils into the liver in a mouse model of endotoxemia. Using dynamic in vivo imaging of the liver, we observed that neutrophil recruitment within the sinusoids and post-sinusoidal venules occurred equivalently between LPS-treated wild-type and CD14-knockout mice. Neutrophil recruitment within the liver was completely independent of CD14 regardless of whether it was expressed on cells of hematopoietic or nonhematopoietic origin or in serum as soluble CD14. Whereas CD14 expression was essential for activation of circulating neutrophils and for the development of LPS-induced systemic inflammation (pulmonary neutrophil sequestration, leukopenia, and increased serum proinflammatory cytokine levels), deficiency of CD14 did not limit the adhesion strength of neutrophils in vitro. Furthermore, wild-type and CD14-knockout mice displayed identical deposition of serum-derived hyaluronan-associated protein within liver sinusoids in response to LPS, indicating that the sinusoid-specific CD44/hyaluronan/serum-derived hyaluronan-associated protein-dependent pathway of neutrophil adhesion is activated independently of CD14. Therefore, the liver microcirculation possesses a unique CD14-independent mechanism of LPS detection and activation of neutrophil recruitment.

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“…In fact, in one report, SchuS4 was not even detected in resident granulocytes during the first day of infection (30). Thus, an additional explanation for the early control of SchuS4 in the lungs and spleens of sCD14-treated animals is that there (63). Similarly, CD14 was found to contribute to mortality and development of pulmonary pathology observed in mice infected with Mycobacterium tuberculosis (62).…”

Section: Discussionmentioning

confidence: 89%

The Presence of CD14 Overcomes Evasion of Innate Immune Responses by VirulentFrancisella tularensisin Human Dendritic Cells In Vitro and Pulmonary Cells In Vivo

Chase¹,

Bosio²

2010

Infect Immun

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Francisella tularensis is a Gram-negative bacterium that causes acute, lethal disease following inhalation. We have previously shown that viable F. tularensis fails to stimulate secretion of proinflammatory cytokines following infection of human dendritic cells (hDC) in vitro and pulmonary cells in vivo. Here we demonstrate that the presence of the CD14 receptor is critical for detection of virulent F. tularensis strain SchuS4 by dendritic cells, monocytes, and pulmonary cells. Addition of soluble CD14 (sCD14) to hDC restored cytokine production following infection with strain SchuS4. In contrast, addition of anti-CD14 to monocyte cultures inhibited the ability of these cells to respond to strain SchuS4. Addition of CD14 or blocking CD14 following SchuS4 infection in dendritic cells and monocytes, respectively, was not due to alterations in phagocytosis or replication of the bacterium in these cells. Administration of sCD14 in vivo also restored cytokine production following infection with strain SchuS4, as assessed by increased concentrations of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), IL-12p70, and IL-6 in the lungs of mice receiving sCD14 compared to mock-treated controls. In contrast to homogenous cultures of monocytes or dendritic cells infected in vitro, mice treated with sCD14 in vivo also exhibited controlled bacterial replication and dissemination compared to mock-treated controls. Interestingly, animals that lacked CD14 were not more susceptible or resistant to pulmonary infection with SchuS4. Together, these data support the hypothesis that the absence or low abundance of CD14 on hDC and in the lung contributes to evasion of innate immunity by virulent F. tularensis. However, CD14 is not required for development of inflammation during the last 24 to 48 h of SchuS4 infection. Thus, the presence of this receptor may aid in control of virulent F. tularensis infections at early, but not late, stages of infection.

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CD14 Impairs Host Defense against Gram‐Negative Sepsis Caused byBurkholderia pseudomalleiin Mice

Abstract: CD14 is crucially involved in the recognition of B. pseudomallei by innate immune cells but plays a remarkable detrimental role in the host response against B. pseudomallei. Inhibition of CD14 may be a novel treatment strategy in melioidosis.

Cited by 33 publications

References 51 publications

CD14 Mediates Toll-like Receptor 4 (TLR4) Endocytosis and Spleen Tyrosine Kinase (Syk) and Interferon Regulatory Transcription Factor 3 (IRF3) Activation in Epithelial Cells and Impairs Neutrophil Infiltration and Pseudomonas aeruginosa Killing in Vivo

CD14 Mediates Toll-like Receptor 4 (TLR4) Endocytosis and Spleen Tyrosine Kinase (Syk) and Interferon Regulatory Transcription Factor 3 (IRF3) Activation in Epithelial Cells and Impairs Neutrophil Infiltration and Pseudomonas aeruginosa Killing in Vivo

The Role of CD14 in Neutrophil Recruitment within the Liver Microcirculation during Endotoxemia

The Presence of CD14 Overcomes Evasion of Innate Immune Responses by VirulentFrancisella tularensisin Human Dendritic Cells In Vitro and Pulmonary Cells In Vivo

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