C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity.
C-reactive protein (CRP) is a serum protein that is massively induced as part of the innate immune response to infection and tissue injury. As CRP has been detected in damaged tissues and is known to activate complement, we assessed whether apoptotic lymphocytes bound CRP and determined the effect of binding on innate immunity. CRP bound to apoptotic cells in a Ca(2+)-dependent manner and augmented the classical pathway of complement activation but protected the cells from assembly of the terminal complement components. Furthermore, CRP enhanced opsonization and phagocytosis of apoptotic cells by macrophages associated with the expression of the antiinflammatory cytokine transforming growth factor beta. The antiinflammatory effects of CRP required C1q and factor H and were not effective once cells had become necrotic. These observations demonstrate that CRP and the classical complement components act in concert to promote noninflammatory clearance of apoptotic cells and may help to explain how deficiencies of the classical pathway and certain pentraxins lead to impaired handling of apoptotic cells and increased necrosis with the likelihood of immune response to self.
Gershov
D
D
Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA.
Kim
S
S
Brot
N
N
Elkon
K B
KB
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D002097:C-Reactive Protein / Q000276:immunology* / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism; D003179:Complement C3b / Q000276:immunology / Q000378:metabolism; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000276:immunology; D019169:Jurkat Cells; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009336:Necrosis; D009895:Opsonin Proteins / Q000276:immunology / Q000494:pharmacology; D010587:Phagocytosis; D011485:Protein Binding / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
C493495:CFH protein, human; D015938:Complement Membrane Attack Complex; D009895:Opsonin Proteins; D016212:Transforming Growth Factor beta; D015922:Complement C1q; D003179:Complement C3b; D017242:Complement Factor H; D002097:C-Reactive Protein; D002118:Calcium