Apoptosis Is Essential for Neutrophil Functional Shutdown and Determines Tissue Damage in Experimental Pneumococcal Meningitis

PLoS Pathogens

Hans Häcker¹  Uwe Koedel²  Bianca Obermaier²  Robert Paul²  Georg Häcker³  Susanne Kirschnek³  Tobias Frankenberg³ 

[1] Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Department of Neurology, Clinic of the University of Munich, Munich, Germany;Institute for Medical Microbiology, Technische Universität München, Munich, Germany

关键词: Neutrophils;    Apoptosis;    Mouse models;    Inflammation;    Antibiotics;    Meningitis;    White blood cells;    Macrophages;   

DOI  :  10.1371/journal.ppat.1000461

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY