ReviewA role of macrophage complement receptor CRIg in immune clearance and inflammation
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.
References (81)
- et al.
Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen
Immunity
(1996) - et al.
Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis
Blood
(2002) - et al.
Macrophages: obligate partners for tumor cell migration, invasion, and metastasis
Cell
(2006) - et al.
Inflammation and insulin resistance
FEBS Lett.
(2008) Complement: a unique innate immune sensor for danger signals
Mol. Immunol.
(2004)- et al.
The alternative pathway of complement activation
Adv. Immunol.
(1976) - et al.
CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens
Cell
(2006) - et al.
Structural insights into the central complement component C3
Mol. Immunol.
(2007) - et al.
Characterization of monoclonal antibody specific to the Z39Ig protein, a member of immunoglobulin superfamily
Immunol. Lett.
(2005) - et al.
Complement receptors
Curr. Opin. Immunol.
(1992)
Cloning of Z39Ig, a novel gene with immunoglobulin-like domains located on human chromosome X
Biochim. Biophys. Acta
Complement analysis in the 21st century
Mol. Immunol.
Identification of residues within the 727–767 segment of human complement component C3 important for its interaction with factor H and with complement receptor 1 (CR1, CD35)
J. Biol. Chem.
Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis
Blood
Role of complement and complement regulators in the removal of apoptotic cells
Mol. Immunol.
Inhibition of beta 2 integrin receptor and Syk kinase signaling in monocytes by the Src family kinase Fgr
Immunity
Z39Ig is co-expressed with activated macrophage genes
Biochim. Biophys. Acta
Functional insights on the polarized redistribution of leukocyte integrins and their ligands during leukocyte migration and immune interactions
Immunol. Rev.
Role of Kupffer cells in host defense and liver disease
Liver Int.
Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies
Nat. Genet.
Hereditary C1q deficiency and systemic lupus erythematosus
Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases
Science
The complement system in regulation of adaptive immunity
Nat. Immunol.
A protective role for innate immunity in systemic lupus erythematosus
Nat. Rev. Immunol.
CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes
Science
Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2
J. Exp. Med.
Mechanisms of disease: the complement system and the pathogenesis of systemic lupus erythematosus
Nat. Clin. Pract. Rheumatol.
Primate erythrocyte-immune complex-clearing mechanism
J. Clin. Invest.
Induction of cell-associated interleukin 1 through stimulation of the adhesion-promoting proteins LFA-1 (CD11a/CD18) and CR3 (CD11b/CD18) of human monocytes
Eur. J. Immunol.
Activation of the human complement alternative pathway by Listeria monocytogenes: evidence for direct binding and proteolysis of the C3 component on bacteria
Infect. Immun.
The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands
J. Cell Biol.
Integrin-dependent phagocytosis-spreading from microadhesion to new concepts
J. Cell Sci.
Complement factor H polymorphism and age-related macular degeneration
Science
The use of laboratory tests in the diagnosis of SLE
J. Clin. Pathol.
Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte
J. Exp. Med.
Characterization of the initial C3 convertase of the alternative pathway of human complement
J. Immunol.
Vav GEFs are required for beta2 integrin-dependent functions of neutrophils
J. Cell Biol.
Analysis of C3 deposition and degradation on bacterial surfaces after opsonization
J. Infect. Dis.
Monocyte and macrophage heterogeneity
Nat. Rev. Immunol.
Complementary adhesion molecules promote neutrophil–Kupffer cell interaction and the elimination of bacteria taken up by the liver
J. Immunol.
Cited by (82)
The biology of VSIG4: Implications for the treatment of immune-mediated inflammatory diseases and cancer
2023, Cancer LettersCitation Excerpt :The importance of VSIG4 in immune homeostasis indicates that VSIG4 fusion protein or adoptively transferred VSIG4+ macrophages might be utilized to treat immune-mediated inflammatory diseases caused by insufficient VSIG4+ macrophages. The suppressive role of VSIG4 in T-cell responses is beneficial for controlling the development of immune-mediated inflammatory diseases but detrimental for anti-tumor immunotherapy through fostering a suppressive tumor microenvironment [14]. The analysis of gene expression signatures of patients with T-cell/histiocyte-rich large B-cell lymphoma reveals that VSIG4 is one of the most significantly up-regulated genes [70], and the gene expression profile of patients with post-transplant diffuse large B-cell lymphoma (PT-DLBCL) also shows that VSIG4 is up-regulated in the EBV + PT-DLBCL group compared with the EBV− group [71].
An overview of complement systems in teleosts
2022, Developmental and Comparative ImmunologyNovel lipid combination for delivery of plasmid DNA to immune cells in the spleen
2021, Journal of Controlled ReleaseFcγ receptors in autoimmunity and end-organ damage
2020, Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects