CD46 plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells.
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.
Elward
Kristina
K
Brain Inflammation and Immunity Group (BI2G), Department of Medical Biochemistry and Immunology, School of Medicine, Heath Park Campus, Cardiff University, Cardiff CF14 4XN, United Kingdom.
Griffiths
Mark
M
Mizuno
Masashi
M
Harris
Claire L
CL
Neal
Jim W
JW
Morgan
B Paul
BP
Gasque
Philippe
P
D017209:Apoptosis; D018957:CD59 Antigens / Q000096:biosynthesis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D003167:Complement Activation; D015922:Complement C1q / Q000378:metabolism; D003165:Complement System Proteins; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007107:Immune System; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D015603:Keratinocytes / Q000166:cytology; D007700:Kinetics; D051916:Membrane Cofactor Protein / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009336:Necrosis; D010718:Phosphatidylserines / Q000737:chemistry; D010766:Phosphorylation; D011951:Receptors, Complement / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism
D018957:CD59 Antigens; D007476:Ionophores; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D010718:Phosphatidylserines; D011951:Receptors, Complement; D015922:Complement C1q; D003165:Complement System Proteins; D006861:Hydrogen Peroxide; D019061:src-Family Kinases; D012260:Ribonucleases