In vivo studies demonstrating a role for HRG in several physiological and pathological conditions
| Properties . | Experimental observations/future directions . | Reference . |
|---|---|---|
| Role of HRG in immunity | ||
| Antifungal | Increased susceptibility to fungal infection in HRG-deficient mice | 40 |
| At pH 5.5 (pathological pH of the wounded or infected foci) and in the presence of zinc, HRG exhibits antifungal activity in a concentration-dependant manner. | ||
| The HRR tethers HRG to the ergosterol-containing cell wall, resulting in lysis of the target cell. | ||
| HRG-deficient mice exposed to Candida albicans have a significantly greater rate of fatality, with exaggerated fungal load in lymphoid organs. | ||
| Antibacterial | HRG protects mice from Streptococcus pryrogenes infection | 38 |
| At pH 5.5, HRG lyses Streptococcus pyrogenes via the HRR. | ||
| The antifibrinolytic properties of HRG enable it to contain bacteria in a fibrin clot and its antibacterial activity may be exerted directly in the clot. | ||
| HRG also orchestrates the containment of bacteria at the infection foci by modulating the chemotaxis of neutrophils/macrophages and the efficient formation of an abscess. | ||
| Endotoxin-neutralizing effects | In vitro data suggest that HRG-deficient mice will be more susceptible to septic shock. | 42 |
| Regulation of T-cell adhesion | In vitro data suggest that HRG-deficient mice will have an altered immune response as the result of a dysregulation in T-cell migration and interaction with antigen presenting cells/endothelium. | 6,43,–45 |
| Apoptotic and necrotic cell clearance | In vitro data suggest that HRG-deficient mice (in particular aged mice) are likely to develop autoimmunity as the result of impairment in apoptotic and necrotic cell uptake. | 22,25,26,33 |
| In vitro data also suggest that HRG-deficient mice may have a delayed response to necrotic cell-induced inflammation. | ||
| Formation of immune complexes | In vitro data suggest that HRG-deficient mice are likely to develop diseases such as arthritis, vasculitis, and glomerulonephritis as the result of an accumulation of insoluble immune complexes. | 18-20,28 |
| Role of HRG in vascular biology | ||
| Proangiogenic (indirect) | HRG inhibits antiangiogenic activity of TSP-1 | 17,46 |
| In both in vivo corneal angiogenesis assay and Matrigel plug assay on C57BL/6 mice, HRG reverses the inhibitory effect of TSP-1 on bFGF-induced neovascularization. | ||
| Inhibition of vasculostatin by CLESH motif on HRG promotes brain tumor formation | ||
| When coexisting at the tumor site, HRG abrogates the antiangiogenic activity of vasculostatin, resulting in enhanced glioblastoma volume in athymic nude mice implanted with LN229 glioma cells subcutaneously or intracranially. | ||
| Histological analysis of mouse brain tumor specimen shows marked level of neovascularization in the presence of HRG. | ||
| Antiangiogenic | HRG inhibits vascularization and tumor establishment | 47,–49 |
| The tumor volume of subcutaneously inoculated T241 fibrosarcoma cells in C57BL/6 mice is significantly reduced by 60%-70% after HRG treatment. The presence of HRG increases the incidence of apoptosis and reduces cell proliferation at the tumor site. | ||
| In a RCAS/TV-A in vivo mouse brain tumor model, HRG impairs growth of experimental glioblastoma with no noticeable effect on cell proliferation. | ||
| By abrogating primary endothelial cell adhesion and rearrangement of focal adhesions in vitro, HRG may inhibit tumor vascularization via the same mechanism in vivo. | ||
| The release of HRR fragments from HRG via proteolytic cleavage is essential for its antichemotactic properties in vivo. | ||
| In a Rip1-Tag2 pancreatic β-cell tumor model, tumor angiogenesis is enhanced in HRG-deficient mice. | ||
| Anticoagulant and antifibrinolytic modifier | Enhanced blood coagulation and fibrinolysis in HRG-deficient mice | 50 |
| The formation of blot clots is enhanced in the absence of plasma HRG because HRG-deficient mice exhibit shorter prothrombin time and shorter bleeding time. | ||
| HRG is antifibrinolytic as the presence of HRG reduces the lysis of fibrin clots. |
| Properties . | Experimental observations/future directions . | Reference . |
|---|---|---|
| Role of HRG in immunity | ||
| Antifungal | Increased susceptibility to fungal infection in HRG-deficient mice | 40 |
| At pH 5.5 (pathological pH of the wounded or infected foci) and in the presence of zinc, HRG exhibits antifungal activity in a concentration-dependant manner. | ||
| The HRR tethers HRG to the ergosterol-containing cell wall, resulting in lysis of the target cell. | ||
| HRG-deficient mice exposed to Candida albicans have a significantly greater rate of fatality, with exaggerated fungal load in lymphoid organs. | ||
| Antibacterial | HRG protects mice from Streptococcus pryrogenes infection | 38 |
| At pH 5.5, HRG lyses Streptococcus pyrogenes via the HRR. | ||
| The antifibrinolytic properties of HRG enable it to contain bacteria in a fibrin clot and its antibacterial activity may be exerted directly in the clot. | ||
| HRG also orchestrates the containment of bacteria at the infection foci by modulating the chemotaxis of neutrophils/macrophages and the efficient formation of an abscess. | ||
| Endotoxin-neutralizing effects | In vitro data suggest that HRG-deficient mice will be more susceptible to septic shock. | 42 |
| Regulation of T-cell adhesion | In vitro data suggest that HRG-deficient mice will have an altered immune response as the result of a dysregulation in T-cell migration and interaction with antigen presenting cells/endothelium. | 6,43,–45 |
| Apoptotic and necrotic cell clearance | In vitro data suggest that HRG-deficient mice (in particular aged mice) are likely to develop autoimmunity as the result of impairment in apoptotic and necrotic cell uptake. | 22,25,26,33 |
| In vitro data also suggest that HRG-deficient mice may have a delayed response to necrotic cell-induced inflammation. | ||
| Formation of immune complexes | In vitro data suggest that HRG-deficient mice are likely to develop diseases such as arthritis, vasculitis, and glomerulonephritis as the result of an accumulation of insoluble immune complexes. | 18-20,28 |
| Role of HRG in vascular biology | ||
| Proangiogenic (indirect) | HRG inhibits antiangiogenic activity of TSP-1 | 17,46 |
| In both in vivo corneal angiogenesis assay and Matrigel plug assay on C57BL/6 mice, HRG reverses the inhibitory effect of TSP-1 on bFGF-induced neovascularization. | ||
| Inhibition of vasculostatin by CLESH motif on HRG promotes brain tumor formation | ||
| When coexisting at the tumor site, HRG abrogates the antiangiogenic activity of vasculostatin, resulting in enhanced glioblastoma volume in athymic nude mice implanted with LN229 glioma cells subcutaneously or intracranially. | ||
| Histological analysis of mouse brain tumor specimen shows marked level of neovascularization in the presence of HRG. | ||
| Antiangiogenic | HRG inhibits vascularization and tumor establishment | 47,–49 |
| The tumor volume of subcutaneously inoculated T241 fibrosarcoma cells in C57BL/6 mice is significantly reduced by 60%-70% after HRG treatment. The presence of HRG increases the incidence of apoptosis and reduces cell proliferation at the tumor site. | ||
| In a RCAS/TV-A in vivo mouse brain tumor model, HRG impairs growth of experimental glioblastoma with no noticeable effect on cell proliferation. | ||
| By abrogating primary endothelial cell adhesion and rearrangement of focal adhesions in vitro, HRG may inhibit tumor vascularization via the same mechanism in vivo. | ||
| The release of HRR fragments from HRG via proteolytic cleavage is essential for its antichemotactic properties in vivo. | ||
| In a Rip1-Tag2 pancreatic β-cell tumor model, tumor angiogenesis is enhanced in HRG-deficient mice. | ||
| Anticoagulant and antifibrinolytic modifier | Enhanced blood coagulation and fibrinolysis in HRG-deficient mice | 50 |
| The formation of blot clots is enhanced in the absence of plasma HRG because HRG-deficient mice exhibit shorter prothrombin time and shorter bleeding time. | ||
| HRG is antifibrinolytic as the presence of HRG reduces the lysis of fibrin clots. |
bFGF indicates basic fibroblast growth factor; HRG, histidine-rich glycoprotein; HRR, histidine-rich region; and TSP-1, thrombospondin-1.