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.