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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-1beta and G-CSF as well as reduced levels of anti-inflammatory TGF-beta. 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.

Background. Recent studies have suggested that, in addition to Toll-like receptor (TLR) 2, other pattern recognition receptors mediate activation of the immune response after infection of the central nervous system (CNS) with Streptococcus pneumoniae (SP). Methods. Using a mouse meningitis model, we investigated the influence of TLR4 single deficiency (TLR4-/-), TLR2/TLR4 double deficiency (TLR2/4-/-), and TLR2/TLR4/TLR9 triple deficiency (TLR2/4/9-/-) on the immune response of the CNS to SP infection. To identify the cell populations that mediate the responses to SP, we generated TLR2/4-/--wild-type (wt) bone marrow (BM) chimeras. Results. Compared with infected wt mice, infected TLR2/4-/- and TLR2/4/9-/- mice had similar reductions in brain cytokine levels, pleocytosis, and cerebral pathologic findings, whereas no such effect was noted in infected TLR4-/- mice. The attenuated immune response was paralleled by an impaired host defense that resulted in worsening of disease. Analysis of the chimeric mice after infection showed that mere TLR2/4 deficiency, either of radioresistant cells or of transplanted BM-derived cells, was sufficient to mount a substantial cerebral immune response, such as that noted in wt mice. Conclusions. In murine SP meningitis, TLR2 and TLR4 expressed on radioresistant and transplanted BM-derived cells were major cellular sensors of invading SP inducing inflammatory responses.

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.