Oxidized Phospholipids Inhibit Phagocytosis and Impair Outcome in Gram-Negative Sepsis In Vivo

Knapp, Sylvia; Matt, Ulrich; Leitinger, Norbert; Poll, Tom van der

doi:10.4049/jimmunol.178.2.993

Cited by 69 publications

(71 citation statements)

References 49 publications

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“…Macrophages have been shown to be key cellular players in the uptake of apoptotic neutrophils and in the resolution of infl ammation ( 35,36 ). Therefore, the possibility existed that the increased infl ammation seen in cathepsin D Ϫ / Ϫ mice percentage of phagocytosed neutrophils was seen between wild-type and cathepsin D Ϫ / Ϫ mice ( Fig.…”

Section: Cathepsin D Defi Ciency Prolongs Innate Immune Responsesmentioning

confidence: 99%

Caspase-8 is activated by cathepsin D-initiating neutrophil apoptosis during the resolution of inflammation

Conus¹,

Perozzo²,

Reinheckel³

et al. 2008

J Cell Biol

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In the resolution of infl ammatory responses, neutrophils rapidly undergo apoptosis. We describe a new proapoptotic pathway in which cathepsin D directly activates caspase-8. Cathepsin D is released from azurophilic granules in neutrophils in a caspase-independent but reactive oxygen species -dependent manner. Under infl ammatory conditions, the translocation of cathepsin D in the cytosol is blocked. Pharmacological or genetic inhibition of cathepsin D resulted in delayed caspase activation and reduced neutrophil apoptosis. Cathepsin D defi ciency or lack of its translocation in the cytosol prolongs innate immune responses in experimental bacterial infection and in septic shock. Thus, we identifi ed a new function of azurophilic granules that is in addition to their role in bacterial defense mechanisms: to regulate the life span of neutrophils and, therefore, the duration of innate immune responses through the release of cathepsin D.

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Section: Cathepsin D Defi Ciency Prolongs Innate Immune Responsesmentioning

confidence: 99%

Caspase-8 is activated by cathepsin D-initiating neutrophil apoptosis during the resolution of inflammation

Conus¹,

Perozzo²,

Reinheckel³

et al. 2008

J Cell Biol

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“…Peritoneal macrophages from untreated TLR2 KO, TLR4 KO, CD14 KO, MyD88 KO, and WT mice (n ϭ 5-8/strain) were harvested by peritoneal lavage with 5 ml of sterile PBS as described (34,35). Total cell numbers were counted from each sample using a hemocytometer.…”

Section: Preparation Of Peritoneal Macrophagesmentioning

confidence: 99%

“…Phagocytosis was evaluated in essence as described previously (34,37). Peritoneal lavage was performed in WT, TLR2 KO, MyD88 KO, and CD14 KO mice (n ϭ 5/strain) using 5 ml of sterile PBS and blood was collected; macrophages were washed, counted, and resuspended in RPMI 1640 at a final concentration of 5 ϫ 10 5 cells/ml.…”

Section: Phagocytosis Assaysmentioning

confidence: 99%

TLR2-Dependent MyD88 Signaling Contributes to Early Host Defense in MurineEnterococcus faeciumPeritonitis

Leendertse

Willems

Giebelen

et al. 2008

The Journal of Immunology

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The incidence of infections with Enterococcus faecium is increasing worldwide. TLRs have been implicated in the recognition of pathogens and the initiation of an adequate innate immune response. We here sought to determine the roles of MyD88, the common adaptor protein involved in TLR signaling, TLR2, TLR4, and CD14 in host defense against E. faecium peritonitis. MyD88 knockout (KO) mice demonstrated an impaired early response to E. faecium peritonitis, as reflected by higher bacterial loads in peritoneal fluid and liver accompanied by a markedly attenuated neutrophil influx into the abdominal cavity. In vitro, not only MyD88 KO macrophages but also TLR2 KO and CD14 KO macrophages displayed a reduced responsiveness to E. faecium. In accordance, transfection of TLR2 rendered human embryonic kidney 293 cells responsive to E. faecium, which was enhanced by cotransfection of CD14. TLR2 KO mice showed higher bacterial loads in peritoneal fluid after in vivo infection with E. faecium and a diminished influx of neutrophils, whereas CD14 KO mice had an unaltered host response. E. faecium phagocytosis and killing were not affected by MyD88, TLR2, or CD14 deficiency. TLR4 did not play a role in the immune response to E. faecium in vitro or in vivo. These data suggest that MyD88 contributes to the effective clearance of E. faecium during peritonitis at least in part via TLR2 and by facilitating neutrophil recruitment to the site of the infection.

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“…Bacterial killing was determined according to a protocol published recently (30,31). Peritoneal lavage was performed in Wt and PAFR Ϫ/Ϫ mice (n ϭ 7) using 5 ml of sterile saline.…”

Section: Bacterial Killing Of P Aeruginosamentioning

confidence: 99%

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Zoelen

Florquin²,

Meijers

et al. 2008

The Journal of Immunology

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Pseudomonas aeruginosa is a major cause of nosocomial pneumonia, which is associated with high morbidity and mortality. Because of its ubiquitous nature and its ability to develop resistance to antibiotics, it is a problematic pathogen from a treatment perspective. Platelet-activating factor receptor (PAFR) is involved in phagocytosis of several pathogens. To determine the role of PAFR in the innate immune response to P. aeruginosa pneumonia, pafr gene-deficient (PAFR−/−) mice and normal wild-type (Wt) mice were intranasally inoculated with P. aeruginosa. PAFR deficiency impaired host defense as reflected by increased bacterial outgrowth and dissemination in mice with a targeted deletion of the PAFR gene. PAFR−/− neutrophils showed a diminished phagocytosing capacity of P. aeruginosa in vitro. Relative to Wt mice, PAFR−/− mice demonstrated increased lung inflammation and injury as reflected by histopathology, relative lung weights and total protein concentrations in bronchoalveolar lavage fluid, which was accompanied by higher levels of proinflammatory cytokines in lung homogenates and plasma. In addition, PAFR deficiency was associated with exaggerated local and systemic activation of coagulation as determined by fibrin staining of lung tissue and pulmonary and plasma concentrations of thrombin-antithrombin complexes and D-dimer. These data suggest that PAFR is an essential component of an effective host response to P. aeruginosa pneumonia, at least partly via its contribution to the phagocytic properties of professional granulocytes. Additionally, our results indicate that PAFR signaling is not essential for the induction of a local and systemic inflammatory and procoagulant response to Pseudomonas pneumonia.

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Oxidized Phospholipids Inhibit Phagocytosis and Impair Outcome in Gram-Negative Sepsis In Vivo

Cited by 69 publications

References 49 publications

Caspase-8 is activated by cathepsin D-initiating neutrophil apoptosis during the resolution of inflammation

Caspase-8 is activated by cathepsin D-initiating neutrophil apoptosis during the resolution of inflammation

TLR2-Dependent MyD88 Signaling Contributes to Early Host Defense in MurineEnterococcus faeciumPeritonitis

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

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