Abstracts (complete list) - Wissenschaft Online

Tobias Frankenberg, Susanne Kirschnek, Hans Häcker, Uwe Koedel, Georg Häcker
Inhibition of apoptosis conserves neutrophil effector function
and can contribute to inflammation in vivo
Neutrophil granulocytes have essential functions during immune responses against
pyogenic bacteria. Following pathogen clearance, neutrophils have to be removed from
sites of infection, a process that may involve apoptosis. We have previously found that
in a murine model of Streptococcus pneumonia-induced meningitis, overexpression of
the anti-apoptotic protein Bcl-2 in the haematopoietic system aggravates inflammationinduced
tissue damage. The continued presence of neutrophils in these mice despite
clearance of bacteria suggested that the block of apoptosis caused sustained pleocytosis
and contributed to the severity of the inflammation. To test this hypothesis, we
compared in vitro apoptosis and effector function of wt and Bcl-2 overexpressing
neutrophils derived from isolated bone-marrow progenitor cells retrovirally transduced
with regulable Hoxb8. In its active state, Hoxb8 promotes progenitor expansion while
upon inactivation permits cellular differentiation. This culture system thus provides the
possibility to generate almost unlimited numbers of ‘near-primary’ neutrophils.
Differentiated Hoxb8 neutrophils displayed the typical nuclear morphology, expressed
Gr-1, and were phagocytosis-proficient. No obvious differences in terms of
differentiation and effector functions were observed between wt and Bcl-2 neutrophils.
Upon prolonged culture the vast majority of differentiated wt neutrophils underwent
apoptosis. The overexpression of Bcl-2 efficiently protected neutrophils from cell death
and, importantly, these ‘undead’ cells retained at least some of their effector functions.
These data show that inhibition of apoptosis can prolong neutrophil lifespan and effector
function, which very likely contributes to the more severe pathology in Streptococcus
pneumonia-induced murine meningitis. This model therefore suggests that granulocyte
apoptosis is an important event for the termination of the innate immune response.