Apoptotic cell-mediated immunoregulation of dendritic cells does not require iC3b opsonization.
A number of recent studies show that activation of CR3 on dendritic cells (DCs) suppresses TLR-induced TNF-alpha and IL-12 production and inhibits effective Ag presentation. Although the proposed physiologic role for these phenomena is immune suppression due to recognition of iC3b opsonized apoptotic cells by CR3, all of the aforementioned investigations used artificial means of activating CR3. We investigated whether iC3b opsonized apoptotic cells could induce the same changes reported with artificial ligands such as mAbs or iC3b-opsonized RBC. We explored the kinetics of iC3b opsonization in two models of murine cell apoptosis, gamma-irradiated thymocytes and cytokine deprivation of the IL-3 dependent cell line BaF3. Using a relatively homogenous population of early apoptotic cells (IL-3 deprived BaF3 cells), we show that iC3b opsonized apoptotic cells engage CR3, but this interaction is dispensable in mediating the anti-inflammatory effects of apoptotic cells. TLR-induced TNF-alpha and IL-12 production by bone marrow-derived DCs occurs heterogeneously, with apoptotic cells inhibiting only certain populations depending on the TLR agonist. In contrast, although apoptotic cells induced homogeneous IL-10 production by DCs, IL-10 was not necessary for the inhibition of TNF-alpha and IL-12. Furthermore, because the ability of iC3b opsonization to enhance phagocytosis of apoptotic cells has been controversial, we report that iC3b opsonization does not significantly affect apoptotic cell ingestion by DCs. We conclude that the apoptotic cell receptor system on DCs is sufficiently redundant such that the absence of CR3 engagement does not significantly affect the normal anti-inflammatory processing of apoptotic cells.
Behrens
Edward M
EM
Laboratory of Dendritic Cell Biology, Division of Rheumatology, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA. behrens@email.chop.edu
Ning
Yue
Y
Muvarak
Nidal
N
Zoltick
Philip W
PW
Flake
Alan W
AW
Gallucci
Stefania
S
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D003179:Complement C3b / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D007700:Kinetics; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009895:Opsonin Proteins / Q000378:metabolism*; D010587:Phagocytosis
D016207:Cytokines; D016177:Macrophage-1 Antigen; D009895:Opsonin Proteins; D003179:Complement C3b