Apoptotic DNA binds to HLA class II molecules inhibiting antigen presentation and participating in the development of anti-inflammatory functional behavior of phagocytic macrophages.
Resident macrophages are mainly responsible for the clearance of apoptotic cells from tissue by phagocytosis. Phagocytosis of apoptotic cells is not accompanied by activation of inflammatory mechanisms, unlike what happens when necrotic phenomena occur. We analyzed the effect of phagocytosis of apoptotic bodies on macrophage cell functions. After phagocytosis of apoptotic cells macrophages were unable to present an exogenous antigen to autologous antigen-specific T-cell lines. The inhibition was mediated by different mechanisms including binding of apoptotic DNA to human leukocyte antigen (HLA) class II molecules of macrophages, decreased expression of co-stimulatory molecules and increased secretion of tumor growth factor beta (TGFbeta). When dendritic cells were cultured with macrophages phagocytosing apoptotic cells, or with their supernatant, impaired dendritic cell antigen presenting activity and reduced tumor necrosis factor alpha (TNFalpha) secretion were found. Our results suggest that: (1) the phagocytosis of apoptotic bodies inhibits macrophage antigen presentation; (2) such inhibition is mediated by the binding of apoptotic DNA to macrophage HLA class II molecules as well as by the activation of biological mechanisms that induce an anti-inflammatory functional behavior in macrophages; and (3) macrophages phagocytosing apoptotic cells inhibit antigen presentation of neighboring dendritic cells via TGFbeta secretion. These events are likely related to the preservation of healthy tissues from the onset of inflammation.
Filaci
Gilberto
G
Department of Internal Medicine and Centro di Eccellenza per le Ricerche Biomediche, University of Genoa, Genoa, Italy.
Contini
Paola
P
Fravega
Marco
M
Fenoglio
Daniela
D
Azzarone
Bruno
B
Julien-Giron
Michel
M
Fiocca
Roberto
R
Boggio
Maurizio
M
Necchi
Vittorio
V
De Lerma Barbaro
Andrea
A
Merlo
Andrea
A
Rizzi
Marta
M
Ghio
Massimo
M
Setti
Maurizio
M
Puppo
Francesco
F
Zanetti
Maurizio
M
Indiveri
Francesco
F
D017951:Antigen Presentation / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology*
D000949:Histocompatibility Antigens Class II