Release of calreticulin from neutrophils may alter C1q-mediated immune functions.
Calreticulin is an abundant intracellular protein which is involved in a number of cellular functions. During cytomegalovirus infection, as well as inflammatory episodes in autoimmune disease, calreticulin can be released from cells and detected in the circulation, where it may act as an immunodominant autoantigen in diseases such as systemic lupus erythematosus. Calreticulin is known to bind to the molecules of innate immunity, such as C1q, the first subcomponent of complement. However, the functional implications of C1q-calreticulin interactions are unknown. In the present study we sought to investigate, in greater detail, the interaction between these two proteins following the release of calreticulin from neutrophils upon stimulation. In order to pinpoint the regions of interaction, recombinant calreticulin and its discrete domains (N-, P- and C-domains) were produced in Escherichia coli. Both the N- and P-domains of calreticulin were shown to bind to the globular head regions of C1q. Calreticulin also appeared to alter C1q-mediated immune functions. Binding of calreticulin to C1q inhibited haemolysis of IgM-sensitized erythrocytes. Both the N- and P-domains of calreticulin were found to contain sites involved in the inhibition of C1q-induced haemolysis. Full-length calreticulin, and its N- and P-domains, were also able to reduce the C1q-dependent binding of immune complexes to neutrophils. We conclude that calreticulin, once released from neutrophils during inflammation, may not only induce an antigenic reaction, but, under defined conditions, may also interfere with C1q-mediated inflammatory processes.
Kishore
U
U
Department of Biochemistry, University of Oxford, U.K.
Sontheimer
R D
RD
Sastry
K N
KN
Zaner
K S
KS
Zappi
E G
EG
Hughes
G R
GR
Khamashta
M A
MA
Strong
P
P
Reid
K B
KB
Eggleton
P
P
D001324:Autoantigens / Q000378:metabolism*; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D037282:Calreticulin; D015922:Complement C1q / Q000378:metabolism* / Q000494:pharmacology; D003171:Complement Pathway, Classical; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*
D001324:Autoantigens; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D015922:Complement C1q