Complement Receptor of the Immunoglobulin Superfamily (CRIg)

Complement Receptor of the Immunoglobulin Superfamily/CRIg Background

Complement receptor of the immunoglobulin family (CRIg), also known as V-set and Ig domain (VSIG4)/B7 family-related protein, is a protein expressed in Kupffer cells. It is a critical receptor for the phagocytosis of opsonised particles in the blood. It recognizes iC3b (inactivated C3b) deposited on microbial surfaces. The unique features of CRIg, as compared with classical complement receptors, CR3 and CR4, have heralded the emergence of new concepts in the regulation of innate and adaptive immunity. Its selective expression in tissue macrophages and dendritic cells has been considered of importance in host defence and in maintaining tolerance against self-antigens. Accumulating evidence from mouse experimental models indicates a potential role for CRIg in protection against bacterial infection and inflammatory diseases, such as rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus, and also in promotion of tumour growth. CRIg expression can be considered as a control point in these diseases, through which inflammatory mediators, including cytokines, act. The ability of CRIg to suppress cytotoxic T cell proliferation and function may underlie its promotion of cancer growth.

Complement Receptor of the Immunoglobulin Superfamily/CRIg Structure

CRIg, a member of the transmembrane protein of the type 1 immunoglobulin (Ig) superfamily, is encoded by the VSIG4 gene located in the pericentromeric region of the human X chromosome. The gene, first documented as "Z39Ig" by Langnaese et al., contains eight exons and has a length of 18.3 kb. In humans, the product, CRIg, referred to as the long form (huCRIg(L), contains both a constant (C2-type) and a variable (V-type) immunoglobulin domain. The huCRIg(S) contains only the V-type immunoglobulin domain, with no C2-type. Only one form of CRIg, containing a single IgV-type domain, is expressed in murine macrophages and the data show that the V-type domain of the CRIg protein is essential for its ability to bind complement components and to promote phagocytosis, whereas the significance of the C2-type domain remains uncertain. .

CRIg Promotes Phagocytosis and Anti-microbial Action of Macrophages

Although there has been limited publication of data showing that complement receptor of the immunoglobulin family (CRIg) plays a role in protection against infection, the results are quite convincing. Using CRIg-/- mice, Helmy et al. showed that CRIg was important in the clearance of the intracellular bacterium Listeria monocytogenes by liver resident/fixed macrophages (Kupffer cells), and preventing dissemination of the bacteria to other organs. This protection provided by CRIg was evident by a reduction in numbers of bacteria and an increase in mouse survival. Similar results were obtained when the extracellular pathogen Staphylococcus aureus was examined, leading to the conclusion that CRIg is required for the rapid clearance of both intracellular and extracellular C3-opsonised bacteria. More recently, the anti-infective actions of CRIg have been demonstrated with adenoviruses in mice.

CRIg functions as a complement receptor on macrophages, promoting phagocytosis by binding to C3b and iC3b-coated particles.CRIg with bound C3b is internalised into Kupffer cells and becomes localised in a pool of constitutively recycling membranes. At the initial stages of phagosome formation, CRIg was actively recruited from recycling endosomes to the sites of C3b-coated particle ingestion. Then, prior to the fusion of the phagosome and lysosome to avoid degradation, CRIg is likely recycled from the phagosome to the endosome for use in further phagocytic events, ensuring a readily available source of CRIg on the cell surface and thereby enabling a faster rate of phagocytosis when bacteria are encountered.

Complement Receptor of the Immunoglobulin Superfamily/CRIg References

1. Helmy K Y, et al. (2006). CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell, 124(5), 915-927.
2. Small A G, et al. (2016). Complement receptor immunoglobulin: a control point in infection and immunity, inflammation and cancer. Swiss medical weekly, 146.
3. Van Lookeren Campagne M, et al. (2007). Macrophage complement receptors and pathogen clearance. Cellular microbiology, 9(9), 2095-2102.
4. He J Q, et al. (2008). A role of macrophage complement receptor CRIg in immune clearance and inflammation. Molecular immunology, 45(16), 4041-4047.
5. Helmy K Y, et al. (2006). CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell, 124(5), 915-927.