Immune activation models: concanavalin A (ConA) and α-galactosylceramide (α-GalCer)
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| Jouan-Lanouet69
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Nec-1 (125 µg I.V.) 15 mins before ConA 20 mg/kg protects at 10 h as well as PARP inhibitor pre-treatment |
Used female mice (most studies have used male mice) |
| Zhou et al.71
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Nec-1 (1.8 mg/kg I.P.) 1 h before ConA (20 mg/kg I.V.) improved mortality compared with ConA alone |
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| Weinlich et al.73
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RIPK3−/− not protected from ConA (same as controls) |
Used control littermates and saw no difference in ConA injury between WT and RIPK3−/− |
| Arshad et al.70
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Nec-1 (125 µg I.V.) given 15 mins before ConA (12 mg/kg I.V.) 10 h, 12 h, 24 h was protective, resulted in less injury, less inflammation and less IL-33 |
Immune cell activation in liver in Nec-1 pretreated animals was not different despite no control for DMSO except for neutrophils which were less with Nec-1 pre-treatment |
| Kang et al.28
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Attenuated liver injury in global RIPK3−/− with α-GalCer |
Global RIPK3−/− resulting in attenuated injury likely because of BM cells and not hepatocytes
RIPK3−/− BM transplanted in Hepatocyte WT animals attenuated injury
Not related to necroptosis but rather impairment of production of cytokines (TNF and IFN-γ) by RIPK3-deficient BM and NKT cells |
| Suda et al.74
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RIPK1 knockdown worsens ConA (10 mg/kg I.V.) injury |
Sub-strain-matched controls no difference between WT and RIPK3−/− (unpublished data) |
| Deutsch et al.46
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Modest protection reported with RIPK3−/− in ConA (20 µg/g I.V.)
Nec-1 (1.65 ug/g, I.P.) pre-treatment daily×3 days, worsened ConA injury and diminished survival
Nec-1 induced worsening of ConA injury was rescued by blocking apoptosis with a pan-caspase inhibitor |
RIPK3−/− resulted in very modest protection against ConA (ALT 2800 versus 2000)
RIPK3−/− slightly delayed death, but overall no mortality difference at 48 h
RIPK3−/− had a better cytokine profile
Confirmed results with Nec-1 s
Single dosing of Nec-1 same effect as three doses before ConA
Inconsistent findings between Nec-1 and RIPK3−/− may suggests this is a necroptosis-independent effect |
| Gunther et al.20
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MLKL−/− protected against ConA (25 mg/kg, I.V.)
Nec-1 s 400 µg (I.P.) 30 min before ConA protected mice
RIPK3−/− mice not protected against ConA
RIPK1 and MLKL expression increased after ConA
RIPK3 not detected in PMH and not upregulated after ConA |
Mechanism of MLKL activation and translocation unclear (unidentified kinase suggested)
RIPK1 upregulated but doesn’t activate MLKL
Much higher dose of Nec-1 than others so difficult to compare |
| Suda et al.74
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RIPK3−/−, MLKL−/−, RIPK1D138N (kinase dead) not protected against α-Gal same injury as strain-matched controls
Nec-1 pre-treatment (1.65 mg/kg I.P.) did NOT protect against α-Gal
RIPK1 knockdown markedly worsens injury (caspase-dependent and blocked by ZVAD, therefore apoptosis) |
The cell death induced in RIPK1 KD mice by α-Gal was blocked by ZVAD (apoptosis) and there was no switch to necroptosis
Kinase dead protein and necrostatin has no effect but knockdown of protein markedly induced apoptosis with α-Gal and worsens injury arguing for a role in the platform function
Littermates not used (sub-strain-matched control)
ASO may have affected NPC as well (confounding and off target effects) |
