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Fas-mediated apoptosis of neutrophils in sera of patients with infection
I E Nwakoby1, K Reddy, P Patel
1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
Abstract:
In the presence of infection, neutropenia is considered to be a marker of poor prognosis; conversely, neutrophilia may not be a determinant of a better prognosis. Since apoptotic neutrophils are compromised functionally, we evaluated the effect of infection on neutrophil apoptosis. The rate of apoptosis was greater for neutrophils isolated from patients with infection than for healthy controls. Escherichia coli did not directly modulate the rate of neutrophil apoptosis. However, sera from infected patients promoted (P < 0.001) neutrophil apoptosis. Interestingly, the sera of patients with different types of infection (gram negative, gram positive, or culture negative) exerted a more or less identical response on neutrophil apoptosis. Sera of infected patients showed a fivefold greater content of FasL compared to controls. Moreover, anti-FasL antibody partly attenuated the infected-serum-induced neutrophil apoptosis. In in vitro studies, E. coli enhanced monocyte FasL expression. Moreover, conditioned media prepared from activated macrophages from control mice showed enhanced apoptosis of human as well as mouse neutrophils. On the contrary, conditioned media prepared from activated macrophages isolated from FasL-deficient mice induced only a mild degree of neutrophil apoptosis. These results suggest that neutrophils in patients with infection undergo apoptosis at an accelerated rate. Infection not only promoted monocyte expression of FasL but also increased FasL content of the serum. Because the functional status of apoptotic cells is compromised, a significant number of neutrophils may not be participating in the body's defense. Since neutrophils play the most important role in innate immunity, their compromised status in the presence of infection may transfer the host defense burden from an innate response to acquired immunity. The present study provides some insight into the lack of correlation between neutrophilia and the outcome of infection.
Insights
Infection accelerates neutrophil apoptosis, impairing the innate immune response. This occurs because infected patient sera and macrophages increase Fas ligand (FasL), leading to premature neutrophil death and reduced defense capabilities.
Area of Science:
- Immunology
- Cell Biology
Background:
- Neutropenia indicates poor prognosis during infection, while neutrophilia does not guarantee a better outcome.
- Apoptotic neutrophils exhibit compromised functionality, impacting their role in host defense.
Purpose of the Study:
- To investigate the effect of infection on neutrophil apoptosis.
- To determine the mechanisms by which infection influences neutrophil apoptosis, particularly the role of Fas ligand (FasL).
Main Methods:
- Neutrophil apoptosis rates were compared between patients with infection and healthy controls.
- The impact of patient sera and bacterial components (Escherichia coli) on neutrophil apoptosis was assessed.
- FasL expression in sera and on monocytes was quantified.
- Experiments using FasL-deficient macrophages were conducted to elucidate the role of FasL in infection-induced apoptosis.
Main Results:
- Neutrophils from infected patients showed a higher rate of apoptosis compared to controls.
- Sera from infected patients significantly promoted neutrophil apoptosis, with increased FasL content.
- Escherichia coli enhanced monocyte FasL expression, and macrophage-conditioned media induced neutrophil apoptosis, dependent on FasL.
- Anti-FasL antibodies partially reduced serum-induced neutrophil apoptosis.
Conclusions:
- Infection accelerates neutrophil apoptosis, partly mediated by increased serum and monocyte-derived FasL.
- This accelerated apoptosis compromises the functional neutrophil pool, potentially shifting the immune response from innate to acquired immunity.
- The findings offer insight into why neutrophilia may not correlate with improved outcomes in infection.
