CD46 Plays a Key Role in Tailoring Innate Immune Recognition of Apoptotic and Necrotic Cells*
- Kristina Elward‡,
- Mark Griffiths‡,
- Masashi Mizuno§,
- Claire L. Harris§,
- Jim W. Neal¶,
- B. Paul Morgan§ and
- Philippe Gasque‡,1
- ‡Brain Inflammation and Immunity Group (BI2G) and §Complement Biology Group, Department of Medical Biochemistry and Immunology, ¶Neuropathology Laboratory, Department of Pathology, School of Medicine, Heath Park Campus, Cardiff University, Cardiff CF14 4XN, United Kingdom
- 1 To whom correspondence should be addressed. Tel.: 44-29-20-745367; Fax: 44-29-20-744305; E-mail: gasque{at}cardiff.ac.uk.
Abstract
Complement is the canonical innate immune system involved in host defense and tissue repair with the clearance of cell debris. In contrast to the robust armory mounted against microbial nonself-pathogens, complement is selectively activated on altered self (i.e. apoptotic and necrotic cells) to instruct the safe demise by poorly characterized mechanisms. Our data shed new light on the role of complement C1q in sensing nucleic acids (NA) rapidly exposed on apoptotic Jurkat T cell membranes and in driving C3 opsonization but without the lytic membrane attack complex. DNA/RNase-treated apoptotic cells failed to activate complement. We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46. CD46 from nuclear and membrane stores was found to cluster into blebs and shed into microparticles together with NA, phosphatidylserine, C1q, and factor H. Classical and alternative pathways of complement were involved in the recognition of H2O2-treated necrotic cells. Membrane attack complex was detected on necrotic cells possibly as a result of CD46 and CD59 shedding into soluble forms. Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites.
Footnotes
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↵2 The abbreviations used are: ACAMPs, apoptotic cell-associated molecular patterns; NA, nucleic acids; MAC, membrane attack complex; DAPI, 4,6-diamidino-2-phenylindole; PPAMPs, pathogenic protein-associated molecular patterns; PAMPs, PAMPS for pathogen-associated molecular patterns; NK, natural killer; FACS, fluorescence-activated cell sorter; PI, propidium iodide; PARP, poly(ADP-ribose) polymerase; Z, benzyloxycarbonyl; FMK, fluoromethyl ketone; FITC, fluorescein isothiocyanate; SAMPs, self-associated molecular patterns; NHS, normal human serum; CR, complement receptor; s, soluble; PS, phosphatidylserine; CRegs, complement regulatory proteins; MBL, mannan-binding lectin.
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↵3 K. Elward and P. Gasque, unpublished observations.
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↵4 K. Elward, C. L. Harris, and P. Gasque, unpublished observations.
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↵* This work was supported by the Medical Research Council (to P. G. and K. E.), the UK Multiple Sclerosis Society (to P. G. and M. G.), and the Wellcome Trust (to C. L. H., M. M., and B. P. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received June 16, 2005.
- Revision received August 3, 2005.
- The American Society for Biochemistry and Molecular Biology, Inc.
