Previous studies indicated that although Kupffer cells express one of the receptors for fragments of C3, complement receptor 3, this receptor does not seem to have a role in the clearance of C3-opsonized pathogens. So, when Helmy et al. found that both human CRIg and mouse CRIg were expressed by Kupffer cells and subsets of macrophages resident in other tissues, they set out to determine whether CRIg was the receptor through which Kupffer cells mediate phagocytosis of C3-opsonized pathogens.
There are two alternative splice variants of human CRIg, a long form and a short form, but only a single form of mouse CRIg, which has 67% sequence homology with the short isoform of human CRIg. All three CRIg proteins were shown to bind soluble forms of the C3 fragments C3b and iC3b, as well as particles opsonized with C3b and iC3b. The in vivo function of CRIg was analysed using mice lacking expression of CRIg. Although these mice had normal numbers of Kupffer cells and other populations of tissue-resident macrophages, CRIg-deficient Kupffer cells did not bind soluble C3b and iC3b, and, compared with wild-type Kupffer cells, had impaired binding to C3-opsonized IgM-coated sheep erythrocytes. Furthermore, Kupffer cells in CRIg-deficient mice that were infected intravenously with either Listeria monocytogenes or Staphylococcus aureus internalized fewer bacteria than did Kupffer cells in similarly infected wild-type mice. In addition, more live bacteria were recovered from the blood, spleen and tissues of infected CRIg-deficient mice. This defect in clearance of pathogens from the circulation resulted in increased levels of serum cytokines in CRIg-deficient mice that were infected intravenously with L. monocytogenes and in increased mortality.
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