Elsevier

Molecular Immunology

Volume 45, Issue 16, October 2008, Pages 4041-4047
Molecular Immunology

Review
A role of macrophage complement receptor CRIg in immune clearance and inflammation

https://doi.org/10.1016/j.molimm.2008.07.011Get rights and content

Abstract

Complement receptor of the immunoglobulin superfamily (CRIg), also referred to as Z39Ig and V-set and Ig domain-containing 4 (VSIG4), has recently been implicated in the clearance of systemic pathogens and autologous cells. CRIg is exclusively expressed on tissue resident macrophages and binds to multimers of C3b and iC3b that are covalently attached to particle surfaces. Next to functioning as an important clearance receptor, CRIg's extracellular domain inhibits complement activation through the alternative, but not the classical, pathway, providing a novel tool to selectively block this pathway in vivo. Here, we review a role for CRIg in immune clearance, T-cell responses and complement regulation, and discuss the implications for disease manifestation.

Introduction

CRIg was first described as a novel gene located on human chromosome X (Langnaese et al., 2000) and expressed highly in lung, placenta and synovium (Lee et al., 2006, Walker, 2002). Accumulating data has now categorized CRIg as a novel member of the complement receptor family, with a unique expression on tissue macrophages and a pivotal function in the clearance of pathogens and autologous cells (Helmy et al., 2006, Kim et al., 2008). In this review, we will present our current understanding of the role of CRIg in the complement system and discuss its importance in regulating innate and adaptive immune responses.

Section snippets

Complement receptors and phagocytosis

Complement, next to mediating opsonization and clearance of pathogens (Gasque, 2004), has also been implicated in the clearance of self-particles, either directly by serving as an apoptotic cell opsonin (Mevorach et al., 1998, Taylor et al., 2000, Trouw et al., 2008) or indirectly through modulating B-cell responses (Carroll, 2004a, Carroll, 2004b). Complement activation occurs through the collaborative action of three pathways, the classical, mannose-binding lectin and the alternative pathway.

Structural basis for CRIg binding to C3b, iC3b and C3c

While most C3b binding partners associate with the alpha chain of C3b (Janssen and Gros, 2007, Oran and Isenman, 1999, Sahu and Lambris, 2001, Taniguchi-Sidle and Isenman, 1994), CRIg binds primarily to the beta chain and not to the alpha chain. The selectivity of CRIg towards C3 fragments rather than native C3, can be explained based on the recently solved structure of CRIg bound to C3b (Wiesmann et al., 2006). The MG3 and MG6 domains of the C3b beta chain contribute 30% and 40% of the total

Role of complement receptors on Kupffer cells (KCs)

The sinusoidal lining of the liver contains the nonparenchymal cell populations consisting of liver macrophages or KCs, sinusoidal endothelial cells and stellate cells. All three cell types play a crucial role in liver homeostasis and in the pathogenesis of liver disease. KCs constitute ∼90% of the tissue macrophages in the reticulo-endothelial system and account for ∼15% of the total liver cell population (Bilzer et al., 2006).

KCs are the first to be exposed to constituents absorbed from the

Regulation of CRIg expression on subsets of macrophages

CRIg is expressed not only on KCs in the liver, but also on interstitial macrophages in the heart, synovial lining macrophages in the joint, foam cells in atherosclerotic plaques and resident peritoneal macrophages (Helmy et al., 2006, Lee et al., 2006, Vogt et al., 2006). Human CRIg is in addition highly expressed on Hofbauer cells in the placenta, on adrenal gland macrophages and on alveolar macrophages (Helmy et al., 2006). The role of CRIg on these subsets of macrophages is unknown, but is

CRIg-mediated cellular responses

Several studies have suggested that complement receptors can activate intracellular signaling pathways during phagocytosis (Couturier et al., 1990, Lee et al., 2006, Rutherford and Schenkein, 1983, Thieblemont et al., 1995). For instance, in vitro stimulation of CR3 on human monocytes activates the NF-κB pathway to enhance viral replication (Thieblemont et al., 1995). So far, little is known about the cellular responses following CRIg engagement by its ligands. Since CRIg and CR3 are

CRIg and adaptive immune responses

In addition to its role as a complement receptor, CRIg has been reported to regulate T-cell proliferation in vitro and in vivo (Vogt et al., 2006). In vitro experiments using CRIg-Ig fusion molecules showed that CRIg is a strong negative regulator of murine and human T-cell proliferation and IL-2 production. In mice immunized with a cytomegalovirus glycoprotein, administration of CRIg-Ig fusion protein resulted in a significant reduction in the number of interferon (IFN)-gamma producing splenic

Complement receptors and clearance of self-antigens

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease influenced by both environmental and genetic factors. The disease manifestation is driven in part by the presence of autoantibodies and immune deposits in multiple organs that cause inflammation (Egner, 2000). Given the importance of CRIg in bacteria and platelet clearance and its ability to bind to iC3b and C3b, CRIg may function by ingesting complement-tagged immune complexes, apoptotic cells or cell remnants, thus preventing

CRIg acts as an inhibitor of the alternative complement pathway

In the alternative complement pathway, C3b, in complex with the serine protease factor Bb, is responsible for the cleavage of the substrates C3 and C5. CRIg binding to the convertase subunit C3b results in the inhibition of complement activation both at the level of the C3 and C5 convertase (Wiesmann et al., 2006). For example, in serum exposed to zymosan particles, CRIg significantly reduced C3a, C5a and C5b,6 formation and inhibited immune cell attraction and lysis of target cells by the

Conclusion

Based on the results from studies in vivo, a prominent role for CRIg in host defense against pathogens in the circulation has been uncovered (Helmy et al., 2006). Recently, it has further been established that CRIg binds to autologous cells opsonized with C3 proteins (Kim et al., 2008), extending CRIg function beyond the host defense against pathogens. CRIg expression is restricted to tissue resident macrophages, cells whose unexplored function ranges from the regulation of fat metabolism (de

Acknowledgements

We would like to thank Dr. Eric Brown for his critical reading of this manuscript and helpful comments, Ian Kasman for the imaging of the mouse liver sections and Lauri Diehl for histopathology support.

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