Abstract
During acute bacterial infections such as meningitis, neutrophils enter the tissue where they combat the infection before they undergo apoptosis and are taken up by macrophages. Neutrophils show pro-inflammatory activity and may contribute to tissue damage. In pneumococcal meningitis, neuronal damage despite adequate chemotherapy is a frequent clinical finding. This damage may be due to excessive neutrophil activity. We here show that transgenic expression of Bcl-2 in haematopoietic cells blocks the resolution of inflammation following antibiotic therapy in a mouse model of pneumococcal meningitis. The persistence of neutrophil brain infiltrates was accompanied by high levels of IL-1β and G-CSF as well as reduced levels of anti-inflammatory TGF-β. Significantly, Bcl-2-transgenic mice developed more severe disease that was dependent on neutrophils, characterized by pronounced vasogenic edema, vasculitis, brain haemorrhages and higher clinical scores. In vitro analysis of neutrophils demonstrated that apoptosis inhibition completely preserves neutrophil effector function and prevents internalization by macrophages. The inhibitor of cyclin-dependent kinases, roscovitine induced apoptosis in neutrophils in vitro and in vivo. In wild type mice treated with antibiotics, roscovitine significantly improved the resolution of the inflammation after pneumococcal infection and accelerated recovery. These results indicate that apoptosis is essential to turn off activated neutrophils and show that inflammatory activity and disease severity in a pyogenic infection can be modulated by targeting the apoptotic pathway in neutrophils.
Highlights
The coordinated termination of immune responses is critical to prevent autoimmunity and immunopathology, and the varying effector systems of the immune response are likely to require different ways for their termination
We know that neutrophils eventually die through apoptosis, the connection between neutrophil apoptosis and inflammation in bacterial infections has not been clear
We show here that the experimental inhibition of neutrophil apoptosis leads to much more severe clinical disease in a mouse model of bacterial meningitis
Summary
The coordinated termination of immune responses is critical to prevent autoimmunity and immunopathology, and the varying effector systems of the immune response are likely to require different ways for their termination. Against bacterial and fungal infections, the first line of defence is formed by neutrophils. There is typically a rapid influx of neutrophils from the blood into the site of infection, which is often followed by the infiltration of monocytes that differentiate into inflammatory macrophages [1]. Neutrophil tissue invasion can be triggered by infection or injury and is mediated especially by lipid chemoattractants such as leukotrienes (for a recent review see [2]). As neutrophils contain or can generate a number of toxic substances and intermediates, it is considered critical that they die by apoptosis, since in the course of apoptotic cell death the plasma membrane stays intact until the dying cell has been ingested by a macrophage [3,4]
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