Summary of phenotypical effects on hemostasis, inflammation, and other systems as seen in various knockout mice
| Knockout type . | Effects on . | ||
|---|---|---|---|
| Hemostasis . | Inflammation . | Other . | |
| Protein S−/− | • Death by coagulopathy with macroscopic blood clots and extensive hemorrhages between E15.5 and E17.5. | Not described | • Vascular development is defective (caused by thrombosis and reduced protein S–dependent Axl signaling).88 |
| • Intravascular and interstitial fibrin depositions. | |||
| • Increased amounts of megakaryocytes in the liver, suggesting peripheral thrombocytopenia.88,93 | |||
| Protein S+/− | • 44% decrease in protein S levels. | Not described | • Defects in vascular development.88 |
| • 53% decrease in APC cofactor activity. | |||
| • FVa-based clotting time is shortened, thrombin generation is elevated, the lag time for thrombin generation is shortened.88,93 | |||
| Protein S−/− in hepatocytes (Alb-Cre/protein Sfl/fl) | • 15% show fibrin depositions in blood vessels. | Not described | Not described |
| • 55% decrease in protein S levels. | |||
| • 47% decrease in APC cofactor activity.88 | |||
| Protein S−/− in endothelial and hematopoietic cells (tie2-Cre/protein Sfl/fl) | • Fibrin depositions in blood vessels (but less severe than in Alb-Cre/protein S1fl/fl). | Not described | Not described |
| • 43% decrease in protein S levels. | |||
| • 49% decrease in APC cofactor activity.88 | |||
| Protein S−/− in vascular smooth muscle cells (Sm22-Cre/protein Sfl/fl/Gas6−/−) | Not described | Not described | • Vascular defects leading to permeation into liver parenchyma.88 |
| Gas6−/− | • The mice are protected against venous and arterial thrombosis but do not display spontaneous bleeding (caused by platelet dysfunction).38 | • Reduced inflammation and reduced myofibroblast activation in the steatotic liver, reducing liver fibrosis.94 | • Elevated vascular permeability.38 |
| • Reduced sequestration of platelets onto endothelium. | • Endothelial cells express less VCAM-1 and ICAM-1 when stimulated with TNF-α than WT. | • Less oligodendrocytes and microglial activation after demyelination.98 | |
| • Reduced thrombosis in models of endotoxinemia and vasculitis.57 | • Reduced sequestration of platelets onto endothelium, of leukocytes onto endothelium, and of platelets to leukocytes. | ||
| • Reduced expression and activity of tissue factor in vascular cells.53 | • Reduced leukocyte extravasation and inflammation in endotoxinemia, vasculitis, and heart transplantation.57 | ||
| • More hypoxia-induced cell death and higher IL-1β and TNF-α expression in murine macrophages.95 | |||
| • More graft-versus-host disease when receiving liver transplantation.96 | |||
| • Less mortality and proteinuria in accelerated nephrotoxic nephritis than in WT mice.64 | |||
| • More stable atherosclerotic plaques by increased fibrosis and fewer macrophages.97 | |||
| Gas6−/−, protein S−/− in retinal cells Prosfl/-/Nes-Cre/Gas6−/−) | Not described | Not described | • Blindness from impaired phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells.31 |
| Tyro3/Axl/Mer−/− | • Recurrent thrombosis and hemorrhages in several tissues (including the brain), associated with the presence of antibodies to phospholipids as seen in autoimmune syndromes.50 | • After ∼4 weeks, spleens and lymph nodes enlarge. | • Spermatogenesis in males defected. |
| • Impaired hemostasis, thrombocytopenia resulting from platelet dysfunction and megakaryocytopoiesis.99 | • After 1 year, the spleens are about 10 times the normal size. | • Testes one third of WT size. | |
| • Hyperproliferation of constitutively activated B and T cells (the latter slightly more). | • Blindness from impaired phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells. | ||
| • Ectopic lymphocytes in every researched organ. | • Young adults: diminished hippocampal long-term potential. | ||
| • Clinical manifestations mimic autoimmune diseases similar to rheumatoid arthritis, pemphigus vulgaris, and SLE. | • Aged: neural degeneration with seizures and paralysis.47 | ||
| • T cells express elevated amounts of IL-2 receptor and lectin CD69. | |||
| • B cells express Fas, CD44, and IFN-γ. | |||
| • Vascular endothelia express ICAM-I. Increased antibody titers can be found on double-stranded DNA, collagen, cardiolipin, phosphatidytidylserine, phosphatidylethanolamine, and phosphatidylinositol. | |||
| • Macrophages produce high levels of IL-12 and MHCII is strongly increased. | |||
| • When given LPS intraperitoneally, LPS-induced TNF-α response doubles in comparison with WT. | |||
| • Inactivation of Mer contributes the most to the previously mentioned scenario.50 | |||
| • Immature NK cell development.63 | |||
| Tyro3−/− | • Reduced thrombus formation. | Not described | • Young adults: diminished hippocampal long-term potential. |
| • Initial platelet aggregation is not reduced, but stabilization of the aggregates is, because of a decrease in outside-in signaling and platelet granule secretion.10 | • Aged: neural degeneration with seizures and paralysis.47 | ||
| Axl−/− | • Reduced thrombus formation. | • Increase in apoptosis in response to flow reduction in carotid artery. | • Elevated vascular permeability. |
| • Initial platelet aggregation is not reduced, but stabilization of the aggregates is, because of a decrease in outside-in signaling and platelet granule secretion.10 | • Impaired vascular remodeling: Increase in CD45+ cells and decrease in VSMC, macrophages, and neutrophils.100 | • Impaired vascular remodeling.100 | |
| • Enhanced inflammation in the CNS because of delayed removal of myelin debris during experimental autoimmune encephalomyelitis.101 | |||
| Merkd or Mer−/− | • Reduced thrombus formation. | • Delayed cell clearance of infused apoptotic cells. | • Blindness from impaired phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells.30,49,82 |
| • Initial platelet aggregation is not reduced, but stabilization of the aggregates is, because of a decrease in outside-in signaling and platelet granule secretion.10,54 | • Animals develop a SLE-like autoimmunity with antibodies to chromatin, DNA, and IgG.74-102 | ||
| • Mice show increased susceptibility and death in response to endotoxic shock. | |||
| • Monocytes stimulated with LPS express more NF-κB and produce more TNF-α.11 | |||
| • NK T cells have a defect in in vivo GC-α–stimulated production of IL-4 and IFN-γ.62 | |||
| • Enhanced B-cell responses in splenic marginal zone.103 | |||
| • Increased migration of macrophages, DCs, plasmacytoid DCs, T cells, and B cells into the peritoneal cavity.104 | |||
| • Increased renal inflammation in nephrotoxic serum–induced nephritis.65 | |||
| • Decreased induction of c-Src and STAT3.105 | |||
| Knockout type . | Effects on . | ||
|---|---|---|---|
| Hemostasis . | Inflammation . | Other . | |
| Protein S−/− | • Death by coagulopathy with macroscopic blood clots and extensive hemorrhages between E15.5 and E17.5. | Not described | • Vascular development is defective (caused by thrombosis and reduced protein S–dependent Axl signaling).88 |
| • Intravascular and interstitial fibrin depositions. | |||
| • Increased amounts of megakaryocytes in the liver, suggesting peripheral thrombocytopenia.88,93 | |||
| Protein S+/− | • 44% decrease in protein S levels. | Not described | • Defects in vascular development.88 |
| • 53% decrease in APC cofactor activity. | |||
| • FVa-based clotting time is shortened, thrombin generation is elevated, the lag time for thrombin generation is shortened.88,93 | |||
| Protein S−/− in hepatocytes (Alb-Cre/protein Sfl/fl) | • 15% show fibrin depositions in blood vessels. | Not described | Not described |
| • 55% decrease in protein S levels. | |||
| • 47% decrease in APC cofactor activity.88 | |||
| Protein S−/− in endothelial and hematopoietic cells (tie2-Cre/protein Sfl/fl) | • Fibrin depositions in blood vessels (but less severe than in Alb-Cre/protein S1fl/fl). | Not described | Not described |
| • 43% decrease in protein S levels. | |||
| • 49% decrease in APC cofactor activity.88 | |||
| Protein S−/− in vascular smooth muscle cells (Sm22-Cre/protein Sfl/fl/Gas6−/−) | Not described | Not described | • Vascular defects leading to permeation into liver parenchyma.88 |
| Gas6−/− | • The mice are protected against venous and arterial thrombosis but do not display spontaneous bleeding (caused by platelet dysfunction).38 | • Reduced inflammation and reduced myofibroblast activation in the steatotic liver, reducing liver fibrosis.94 | • Elevated vascular permeability.38 |
| • Reduced sequestration of platelets onto endothelium. | • Endothelial cells express less VCAM-1 and ICAM-1 when stimulated with TNF-α than WT. | • Less oligodendrocytes and microglial activation after demyelination.98 | |
| • Reduced thrombosis in models of endotoxinemia and vasculitis.57 | • Reduced sequestration of platelets onto endothelium, of leukocytes onto endothelium, and of platelets to leukocytes. | ||
| • Reduced expression and activity of tissue factor in vascular cells.53 | • Reduced leukocyte extravasation and inflammation in endotoxinemia, vasculitis, and heart transplantation.57 | ||
| • More hypoxia-induced cell death and higher IL-1β and TNF-α expression in murine macrophages.95 | |||
| • More graft-versus-host disease when receiving liver transplantation.96 | |||
| • Less mortality and proteinuria in accelerated nephrotoxic nephritis than in WT mice.64 | |||
| • More stable atherosclerotic plaques by increased fibrosis and fewer macrophages.97 | |||
| Gas6−/−, protein S−/− in retinal cells Prosfl/-/Nes-Cre/Gas6−/−) | Not described | Not described | • Blindness from impaired phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells.31 |
| Tyro3/Axl/Mer−/− | • Recurrent thrombosis and hemorrhages in several tissues (including the brain), associated with the presence of antibodies to phospholipids as seen in autoimmune syndromes.50 | • After ∼4 weeks, spleens and lymph nodes enlarge. | • Spermatogenesis in males defected. |
| • Impaired hemostasis, thrombocytopenia resulting from platelet dysfunction and megakaryocytopoiesis.99 | • After 1 year, the spleens are about 10 times the normal size. | • Testes one third of WT size. | |
| • Hyperproliferation of constitutively activated B and T cells (the latter slightly more). | • Blindness from impaired phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells. | ||
| • Ectopic lymphocytes in every researched organ. | • Young adults: diminished hippocampal long-term potential. | ||
| • Clinical manifestations mimic autoimmune diseases similar to rheumatoid arthritis, pemphigus vulgaris, and SLE. | • Aged: neural degeneration with seizures and paralysis.47 | ||
| • T cells express elevated amounts of IL-2 receptor and lectin CD69. | |||
| • B cells express Fas, CD44, and IFN-γ. | |||
| • Vascular endothelia express ICAM-I. Increased antibody titers can be found on double-stranded DNA, collagen, cardiolipin, phosphatidytidylserine, phosphatidylethanolamine, and phosphatidylinositol. | |||
| • Macrophages produce high levels of IL-12 and MHCII is strongly increased. | |||
| • When given LPS intraperitoneally, LPS-induced TNF-α response doubles in comparison with WT. | |||
| • Inactivation of Mer contributes the most to the previously mentioned scenario.50 | |||
| • Immature NK cell development.63 | |||
| Tyro3−/− | • Reduced thrombus formation. | Not described | • Young adults: diminished hippocampal long-term potential. |
| • Initial platelet aggregation is not reduced, but stabilization of the aggregates is, because of a decrease in outside-in signaling and platelet granule secretion.10 | • Aged: neural degeneration with seizures and paralysis.47 | ||
| Axl−/− | • Reduced thrombus formation. | • Increase in apoptosis in response to flow reduction in carotid artery. | • Elevated vascular permeability. |
| • Initial platelet aggregation is not reduced, but stabilization of the aggregates is, because of a decrease in outside-in signaling and platelet granule secretion.10 | • Impaired vascular remodeling: Increase in CD45+ cells and decrease in VSMC, macrophages, and neutrophils.100 | • Impaired vascular remodeling.100 | |
| • Enhanced inflammation in the CNS because of delayed removal of myelin debris during experimental autoimmune encephalomyelitis.101 | |||
| Merkd or Mer−/− | • Reduced thrombus formation. | • Delayed cell clearance of infused apoptotic cells. | • Blindness from impaired phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells.30,49,82 |
| • Initial platelet aggregation is not reduced, but stabilization of the aggregates is, because of a decrease in outside-in signaling and platelet granule secretion.10,54 | • Animals develop a SLE-like autoimmunity with antibodies to chromatin, DNA, and IgG.74-102 | ||
| • Mice show increased susceptibility and death in response to endotoxic shock. | |||
| • Monocytes stimulated with LPS express more NF-κB and produce more TNF-α.11 | |||
| • NK T cells have a defect in in vivo GC-α–stimulated production of IL-4 and IFN-γ.62 | |||
| • Enhanced B-cell responses in splenic marginal zone.103 | |||
| • Increased migration of macrophages, DCs, plasmacytoid DCs, T cells, and B cells into the peritoneal cavity.104 | |||
| • Increased renal inflammation in nephrotoxic serum–induced nephritis.65 | |||
| • Decreased induction of c-Src and STAT3.105 | |||
APC, antigen-presenting cell; CNS, central nervous system; MHC, major histocompatibility complex; NK, natural killer; VSMC, vascular smooth muscle cell; WT, wild-type.