Modulation of the Bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages.
This study examined the fate of dendritic cells (DCs) and macrophages (M Phi) in vivo in a murine model of sepsis. Wild-type, knockout, and transgenic mice were used to examine the role of Bcl-2 family members on the regulation of splenic DCs and M Phi survival. Bim knockout (Bim) mice and mice overexpressing Bcl-2 in selected hematopoietic cells were used: (a) overexpression of Bcl-2 in all hematopoietic cells using a vav promoter (Vav-Bcl-2) and (b) overexpression of Bcl-2 in all Major histocompatibility complex (MHC) class I cells (H-2K-Bcl-2). Mice underwent sham surgery or cecal ligation and puncture, and absolute numbers of splenic DCs and M Phi were determined. Importantly, two distinct M Phi populations, that is, well-differentiated "mature" M Phi population and a less differentiated "immature," "monocyte-like" (IM Phi) population were identified that demonstrated differential susceptibility to apoptosis. In wild-type mice, sepsis induced a 64% +/- 7% and a 77% +/- 3% decrease in absolute cell numbers of splenic DCs and IM Phi, respectively (n = 7, P < 0.05). Mature M Phi were not depleted in sepsis. No significant cell depletion was evident in Vav-Bcl-2, H-2K-Bcl-2, or Bim mice. We conclude that sepsis induces a major depletion of developing M Phi as well as DCs, and this depletion may be an important mechanism of immune suppression in sepsis.
Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA.
Octavia M
OM
Peck-Palmer
Jacqueline
J
Unsinger
Katherine C
KC
Chang
Jacquelyn S
JS
McDonough
Harris
H
Perlman
Jonathan E
JE
McDunn
Richard S
RS
Hotchkiss
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D018805:Sepsis / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000473:pathology
D019253:Proto-Oncogene Proteins c-bcl-2