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.
Peck-Palmer
Octavia M
OM
Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA.
Unsinger
Jacqueline
J
Chang
Katherine C
KC
McDonough
Jacquelyn S
JS
Perlman
Harris
H
McDunn
Jonathan E
JE
Hotchkiss
Richard S
RS
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