Apoptosis is essential for neutrophil functional shutdown and determines tissue damage in experimental pneumococcal meningitis.
Apoptosis is essential for neutrophil functional shutdown and determines tissue damage in experimental pneumococcal meningitis.
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DOI：
10.1371/journal.ppat.1000461
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发表时间：
2009-05
期刊：
影响因子：
6.7
通讯作者：
Häcker G
中科院分区：
文献类型：
--
作者：
Koedel U;Frankenberg T;Kirschnek S;Obermaier B;Häcker H;Paul R;Häcker G
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. Infections are typically accompanied by inflammation and the presence of leucocytes at the infected site. Especially in pyogenic (pus generating) infections, neutrophils are the main leukocytes that arrive and that combat the infection. When the bacteria have been killed, the inflammation also has to be resolved, and this resolution involves the death of the neutrophils through the process of apoptosis. Although we know that neutrophils eventually die through apoptosis, the connection between neutrophil apoptosis and inflammation in bacterial infections has not been clear. In meningitis, bacteria gain access to the space surrounding the brain, multiply and cause inflammation. Despite antibiotic therapy, human pneumococcal meningitis often causes brain damage and death of the patient. We show here that the experimental inhibition of neutrophil apoptosis leads to much more severe clinical disease in a mouse model of bacterial (pneumococcal) meningitis. This was due to a prolonged inflammatory activity of the neutrophils. Experimental induction of neutrophil apoptosis in mice that had been infected and treated with antibiotics (mimicking human meningitis) improved the clinical condition and accelerated recovery. Experimental manipulation of neutrophil apoptosis can therefore be beneficial in acute inflammation.
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影响因子：
14.5
作者：
Koedel, U;Rupprecht, T;Kirschning, CJ
通讯作者：
Kirschning, CJ
影响因子：
14.5
作者：
Malipiero, Ursula;Koedel, Uwe;Fontana, Adriano
通讯作者：
Fontana, Adriano
DOI：
10.1073/pnas.2336198100
发表时间：
2003-11-25
影响因子：
11.1
作者：
Pellegrini, M;Belz, G;Strasser, A
通讯作者：
Strasser, A
影响因子：
15.3
作者：
TUOMANEN, EI;SAUKKONEN, K;WRIGHT, SD
通讯作者：
WRIGHT, SD
影响因子：
56.9
作者：
Bouillet, P;Metcalf, D;Strasser, A
通讯作者：
Strasser, A