CRIg clears out the bad guys

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CRIg, a Complement Receptor of the Immunoglobulin superfamily, is required for the efficient phagocytosis of circulating pathogens by Kupffer cells.

Pathogens in the circulation that become coated with fragments of complement component 3 (C3) — a process known as C3 opsonization — are phagocytosed by Kupffer cells (liver-resident macrophages) and are thereby cleared from the host. A report published recently in Cell has now identified a new complement receptor, complement receptor of the immunoglobulin superfamily (CRIg; also known as Z39Ig), as the receptor that is required for this efficient phagocytosis of C3-opsonized pathogens by Kupffer cells.

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.

Mechanistically, it was shown that CRIg on the surface of Kupffer cells is constitutively being internalized and then recycled back to the cell surface. Consistent with this finding, internalized CRIg was observed to colocalize with transferrin, which is a marker of recycling endosomes, and not with lysosomal-associated membrane protein 1, which is a marker of lysosomes. Further analysis showed that during phagocytosis of C3-opsonized particles, CRIg is recruited to the forming phagosome but returns to the recycling endosomes before, or during, phagosome–lysosome fusion.

This study identifies CRIg as the main receptor expressed by Kupffer cells for pathogens opsonized with C3 fragments that induces phagocytosis, and thereby clearance, of these pathogens. As such, CRIg functions as a key mediator of the first line of host defence against systemic infections.

Karen Honey

References

Helmy, K. Y. et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124, 915–927 (2006) | Article | PubMed |