Molecular control of neutrophil apoptosis

Akgül, Cahit; Moulding, Dale; Edwards, Steven W.

doi:10.1016/s0014-5793(00)02324-3

Cited by 450 publications

(467 citation statements)

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“…1 Several cytokines or chemotactic factors, such as interleukin (IL)-8 and keratinocyte chemoattractant (KC) released by macrophages or endothelial cells induce migration of neutrophils to inflammatory sites; 2 an excessive number of neutrophils also migrate to distant organs such as the lung. In addition, pro-inflammatory mediators, such as cytokines or lipopolysaccharide (LPS), prolong the neutrophil lifespan to several days by delaying spontaneous apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, migrated neutrophils in distant organs are activated and release pro-inflammatory mediators excessively by delaying apoptosis. 2 The large amount of toxic reactive oxygen species and granule enzymes released from neutrophils can cause catastrophic collateral damage to host tissues. 3 Interleukin-18 is a pro-inflammatory cytokine that induces γ-interferon (IFN-γ) production; IL-18 is also known as an inflammasome that is activated by the caspase-1 pathway.…”

Section: Introductionmentioning

confidence: 99%

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Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

Takahara

Ishikawa

Shuno

et al. 2013

Acute Medicine & Surgery

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Background: Overactivated neutrophils are causes of acute lung injury, which is a major clinical problem with significant morbidity and mortality in sepsis. Serum interleukin (IL)-18 levels correspond to severity of systemic inflammation.Aim: To elucidate the roles of endogenous IL-18 in lung injury during endotoxin-induced systemic inflammation. Methods: Wild-type (WT) and IL-18 gene knockout (KO) mice were injected with lipopolysaccharide (40 mg/kg) intraperitoneally and killed. Lungs were collected at 0 and 12 h to assess mRNA for intercellular adhesion molecule (ICAM)-1, inducible nitric oxide synthase, myeloperoxidase, immunohistochemistry (cleaved caspase-3, 8-hydroxy-2-deoxyguanosine), and wet/dry ratio. Blood was collected at 0, 1, 12, 18, and 24 h to assess plasma cytokine levels. Results:The survival rates at 24 h were approximately 43% and 76% in the WT and KO mice, respectively. Plasma IL-18 levels were induced time-dependently only in the WT mice. Plasma interferon-γ levels were significantly higher in the WT than in the KO mice at 12 h, but IL-6 and tumor necrosis factor-α levels did not differ between the WT and KO mice. At 12 h, the WT mice showed higher myeloperoxidase activity (P < 0.05), ICAM-1, and wet/dry ratios than KO mice. Cleaved caspase-3 positive neutrophils, which migrated in the lung interstitium, were lower in WT mice than in KO mice.Conclusions: Endogenous IL-18 induced neutrophil accumulation, accompanied by induction of ICAM-1 expression, inhibition of neutrophil apoptosis, and increased inducible nitric oxide synthase-induced oxidative tissue injury in the lung, leading to lung edema and poor outcome during endotoxemia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

Takahara

Ishikawa

Shuno

et al. 2013

Acute Medicine & Surgery

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“…When neutrophils are cultured in vitro, they rapidly undergo spontaneous apoptosis (27,28). In freshly isolated neutrophils Ͼ99% of the cells exhibited high mitochondrial membrane potential, as indicated by JC-1 staining revealing J-aggregates (red) and JC-1 monomers (green; Fig.…”

Section: Changes In Mitochondrial Function During Apoptosismentioning

confidence: 99%

The Mitochondrial Network of Human Neutrophils: Role in Chemotaxis, Phagocytosis, Respiratory Burst Activation, and Commitment to Apoptosis

Fossati

Moulding

Spiller

et al. 2003

The Journal of Immunology

312

251

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It is commonly assumed that human neutrophils possess few, if any, functional mitochondria and that they do not depend on these organelles for cell function. We have used the fluorescent mitochondrial indicators, JC-1, MitoTracker Red, and dihydrorhodamine 123 to show that live neutrophils possess a complex mitochondrial network that extends through the cytoplasm. The membrane potential of these mitochondria was rapidly (within 2 min) disrupted by the addition of FCCP (IC50 = 20 nM), but not by the Fo-ATPase inhibitor, oligomycin (at up to 7 μg/ml). However, inhibition of mitochondrial function with both agents resulted in cell shape changes. Neither activation of the respiratory burst nor phagocytosis of either latex particles or serum-opsonized Staphylococcus aureus was affected by the addition of FCCP or oligomycin. However, FCCP inhibited chemotaxis at concentrations that paralleled disruption of mitochondrial membrane potential. Furthermore, prolonged (2-h) incubation with oligomycin resulted in an impaired ability to activate a respiratory burst and also inhibited chemotaxis. These observations indicate that intact mitochondrial function is required to sustain some neutrophil functions, but not for the rapid initiation of the respiratory burst or phagocytosis. Loss of mitochondrial membrane potential was a very early marker for commitment of neutrophils into apoptosis and preceded the appearance of phosphatidylserine on the cell surface. However, inhibition of mitochondrial function did not accelerate the rate of neutrophil apoptosis. These data shed important insights into the hitherto unrecognized importance of mitochondria in the function of neutrophils during infection and inflammation.

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“…Neutrophils constitutively express pro-apoptotic proteins, while the expression of antiapoptotic Bcl-2 members is very low or undetectable in resting cells. These anti-apoptotic proteins are highly and transiently expressed when neutrophils are exposed to survival factors, like IL-8 and GM-CSF (Akgul 2001, Maianski et al 2003.…”

Section: Hemolytic Episodes and Inflammationmentioning

confidence: 99%