CRIg: A Macrophage Complement Receptor Required for Phagocytosis of Circulating Pathogens

Abstract

The complement system serves an important role in clearance of pathogens, immune complexes, and apoptotic cells present in the circulation. Complement fragments deposited on the particle surface serve as targets for complement receptors present on phagocytic cells. Although Kupffer cells, the liver resident macrophages, play a dominant role in clearing particles in circulation, complement receptors involved in this process have yet to be identified. Here we report the identification and characterization of a Complement Receptor of the Immunoglobulin superfamily, CRIg, that binds complement fragments C3b and iC3b. CRIg expression on Kupffer cells is required for efficient binding and phagocytosis of complement C3-opsonized particles. In turn, Kupffer cells from CRIg-deficient mice are unable to efficiently clear C3-opsonized pathogens in the circulation, resulting in increased infection and mortality of the host. CRIg therefore represents a dominant component of the phagocytic system responsible for rapid clearance of C3-opsonized particles from the circulation.

Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy

“…macrophages, we isolated bone marrow-derived macrophages (BMDMs) from Vsig4 C/C and vsig4 ¡/¡ C57BL/6 mice. 18 We first normalized numbers of LM taken up by the 2 strains, Vsig4 C/C and vsig4 ¡/¡ BMDM, and found that opsonization of LM increased LM uptake rate 2.5 fold more in the Vsig4 C/C BMDMs than in the vsig4 ¡/¡ BMDMs (Fig. 6A).…”

“…The C3b cleavage product of C3 (complement component 3) is a ligand for the VSIG4 receptor 18 and therefore, VSIG4 can be triggered by infecting macrophages with opsonized Listeria monocytogenes (opLM) because the opsonized bacterial membrane is covered with C3b. We examined whether natural triggering of VSIG4 with opLM induced autophagosome formation in macrophages.…”

“…[13][14][15] Autophagy can function as a degradation system detecting microbes that invade the cytosol of the host cell, and can also modulate innate and adaptive immunity, transcriptional signatures for inflammation, and the production and secretion of cytokines including type I IFN. 16,17 VSIG4/CRIg,(V-set and immunoglobulin domain containing 4) is a 50-kDa type I transmembrane receptor that is specifically expressed on monocytes, macrophages, and dendritic cells, 18,19 and is a receptor for the C3b cleavage product of C3 (complement component 3) and inactivated C3b (iC3b). Therefore, complement-opsonized microbes can be efficiently recognized and phagocytosed by VSIG4-expressing macrophages.…”

“…Therefore, complement-opsonized microbes can be efficiently recognized and phagocytosed by VSIG4-expressing macrophages. 18 In addition, VSIG4 cross-linked by an agonistic antibody rapidly translocates to bacteria-containing phagosomes and enhances the acidification of the phagosomes before the bacteria can escape, and this process requires CLIC3 (chloride intracellular channel protein 3). 20 VSIG4 has been reported to regulate T-cell proliferation in vitro and in vivo, 21 and a soluble form of HsVSIG4 displays therapeutic potential in mouse models of arthritis by inhibiting autoreactive immune responses.…”

Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

“…Initially, VSIG4 (CRIg) was described as a complement receptor necessary for binding enzymatic products of C3 and for effective phagocytosis by Kupffer cells (41). In addition, VSIG4 has been also been found to reduce T cell proliferation by CD3/CD28 stimulation in vitro, and to blunt CD8 T cell responses and IFN-␥ production in vivo (42).…”