Persistence of apoptotic cells without autoimmune disease or inflammation in CD14-/- mice.
Interaction of macrophages with apoptotic cells involves multiple steps including recognition, tethering, phagocytosis, and anti-inflammatory macrophage responses. Defective apoptotic cell clearance is associated with pathogenesis of autoimmune disease. CD14 is a surface receptor that functions in vitro in the removal of apoptotic cells by human and murine macrophages, but its mechanism of action has not been defined. Here, we demonstrate that CD14 functions as a macrophage tethering receptor for apoptotic cells. Significantly, CD14(-/-) macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process. However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14(-/-) macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells. We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.
Devitt
Andrew
A
Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.
Parker
Kate G
KG
Ogden
Carol Anne
CA
Oldreive
Ceri
C
Clay
Michael F
MF
Melville
Lynsey A
LA
Bellamy
Christopher O
CO
Lacy-Hulbert
Adam
A
Gangloff
Sophie C
SC
Goyert
Sanna M
SM
Gregory
Christopher D
CD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology*; D019556:COS Cells; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D015759:Ionomycin / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D013997:Time Factors
D018950:Lipopolysaccharide Receptors; D015759:Ionomycin; D003907:Dexamethasone