Protective role of V-set and immunoglobulin domain-containing 4 expressed on kupffer cells during immune-mediated liver injury by inducing tolerance of liver T- and natural killer T-cells

Abstract

V-set and Ig domain-containing 4 (VSIG4, CRIg, or Z39Ig), a newly identified B7-related cosignaling molecule, is a complement receptor and a coinhibitory ligand that negatively regulates T-cell immunity. Despite its exclusive expression on liver Kupffer cells (KCs) that play key roles in liver tolerance, the physiological role of VSIG4 in liver tolerance remains undefined. Mice lacking VSIG4 had poor survival rates and severe liver pathology in a concanavalin A (ConA)-induced hepatitis (CIH) model, which could be prevented by adoptive transfer of VSIG4 1 KCs. The absence of VSIG4 rendered endogenous liver Tand natural killer T (NKT)-cells more responsive to antigen-specific stimulation and impaired tolerance induction in those cells against their cognate antigens. T-cell costimulation with VSIG4.Ig suppressed Th1-, Th2-, and Th17-type cytokine production and arrested the cell cycle at the G 0 /G 1 phase but did not induce apoptosis in vitro. VSIG4-mediated tolerance induction and cell-cycle arrest were further supported by down-regulation of G 1 phase-specific Cdk2, Cdk4, and Cdk6, and up-regulation of tolerance-inducing p27 KIP-1 in VSIG4.Ig-stimulated T-cells. Administration of soluble VSIG4.Ig to wildtype mice prevented CIH development and prolonged the survival of mice with established CIH. Conclusion: Collectively, our results suggest that VSIG4 1 KCs play a critical role in the induction and maintenance of liver T-and NKT-cell tolerance, and that modulation of the VSIG4 pathway using a VSIG4.Ig fusion protein may provide useful immunological therapies against immune-mediated liver injury including autoimmune hepatitis.

CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

“…In mice, F4/80 hi resident macrophages disappear during acute inflammation, while infiltrating monocytes augment the macrophage compartment, so alterations in relative macrophage proportions may simply be indicative of peritoneal inflammation in patients. CRIg itself is a multifunctional protein that promotes phagocytosis of C3-opsonized microbes and apoptotic cells in conjunction with CR3, enhances killing of intracellular bacteria (40), and also possesses antiinflammatory and immunosuppressive functions (19,20,22,(41)(42)(43)(44). CRIg hi macrophages may beneficial due to their superior phagocytic and microbicidal capacity, due to other antiinflammatory functions mediated by CRIg, or for reasons unrelated to CRIg expression.…”

Kupffer-cell-expressed transmembrane TNF-α is a major contributor to lipopolysaccharide and D-galactosamine-induced liver injury

“…Liver KCs and hepatocytes were isolated by the collagenase digestion technique with some modifications (Kuboki et al 2007;Jung et al 2012). Briefly, mouse liver was perfused in situ for 5 min with Hank's buffered salt solution containing 0.05 % collagenase and then excised, minced, and passed through a 70-μm stainless steel mesh.…”

“…Seven days after tail vein injection of 3×10 6 KCs-2h or KCs-6h into mice (Jung et al 2012), LPS (10 μg/kg) plus D-gal (500 mg/kg) were intraperitoneally injected into each group of mice (n=4). Liver tissues and blood samples were then collected 4 h postinjection.…”

Protein Kinase Cα Regulates the Expression of Complement Receptor Ig in Human Monocyte–Derived Macrophages

“…The immunosuppressive action of CRIg on T cells has also been highlighted (10,11). Others have reported its anti-inflammatory properties in experimental autoimmune uveoretinitis (12), intestinal ischemia/reperfusion-induced injury (9), and immune-mediated liver injury (13). Thus identification of mediators that regulate CRIg expression should provide better insights into understanding the inflammatory reaction.…”