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

Abstract

VSIG4/CRIg (V-set and immunoglobulin domain containing 4) is a transmembrane receptor of the immunoglobulin superfamily that is expressed specifically on macrophages and mature dendritic cells. VSIG4 signaling accelerates phagocytosis of C3-opsonized bacteria, thereby efficiently clearing pathogens within macrophages. We found that VSIG4 signaling triggered by C3-opsonized Listeria (opLM) or by agonistic anti-VSIG4 monoclonal antibody (mAb) induced macrophages to form autophagosomes. VSIG4-induced autophagosomes were selectively colocalized with the intracellular LM while starvation-induced autophagosomes were not. Consistent with these results, the frequency of autophagosomes induced by infection with opLM was lower in VSIG4-deficient bone marrow-derived macrophages (BMDMs) than in WT BMDMs. Furthermore, when VSIG4 molecules were overexpressed in HeLa cells, which are nonmacrophage cells, VSIG4 triggering led to efficient uptake of LM, autophagosome formation, and killing of the infected LM. These findings suggest that VSIG4 signaling not only promotes rapid phagocytosis and killing of C3-opsonized intracellular bacteria, as previously reported, but also induces autophagosome formation, eliminating the LM that have escaped from phagosomes. We conclude that VSIG4 signaling provides an anti-immune evasion mechanism that prevents the outgrowth of intracellular bacteria in macrophages.

Novel mechanisms and functions of complement

“…Moreover VSIG4 was recently shown to function as a pattern-recognition receptor for lipoteichoic acid, thereby enabling Kuppfer cells to capture and eliminate circulating Gram-positive bacteria in the liver 45 . Another study has shown that VSIG4 can moreover induce autophagosome formation for eliminating C3-opsonized Listeria monocytogenes that has escaped from phagosomes 46 . This intracellular anti-evasion mechanism may not involve intracellular complement since the VSIG4 signal by itself (activated extracellularly by C3-opsonized bacteria or by agonistic antibody) is sufficient to induce autophagosome formation.…”

Regulation of anti-microbial autophagy by factors of the complement system

“…VSIG4 also participates in the efficient acidification of bacteria-containing vesicles through the modulation of the CLIC3 channel protein [76]. Recently, VSIG4 signaling was in fact found to also promote LC3 lipidation and structuration of LC3-positive puncta during infection of macrophage-like J774 cells by C3-coated L. monocytogenes [77]. Similar to CD46, the crosslinking of VSIG4 with specific monoclonal antibodies is sufficient to cause formation of LC3-II and puncta accumulation in THP1 or J774 macrophage-like cells.…”

Complement Receptors in Myeloid Cell Adhesion and Phagocytosis

“…CD46 shares activities with CR1 in that it binds C3b and C4b, and protects host cells from complement mediated damage. Its intriguing that VSIG4, which protects the vascular system from alternative pathway activation by clearing hydrolyzed C3 from the blood and preventing its association with C5 (10), is also a negative regulator of T cell function (11,92,121,122). The high expression of VSIG4 in the liver and peritoneal cavity may help establish a level of immune privilege in these sites (123), although the role of VSIG4 has not been investigated.…”