α-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-α but Independent of Kupffer Cells

Abstract

NKT cells expressing phenotypic markers of both T and NK cells seem to be pivotal in murine models of immune-mediated liver injury, e.g., in Con A-induced hepatitis. Also α-galactosylceramide (α-GalCer), a specific ligand for invariant Vα14 NKT cells, induces hepatic injury. To improve the comprehension of NKT-cell mediated liver injury, we investigated concomitants and prerequisites of α-GalCer-induced hepatitis in mice. Liver injury induced by α-GalCer injection into C57BL/6 mice was accompanied by intrahepatic caspase-3 activity but appeared independent thereof. α-GalCer injection also induces pronounced cytokine responses, including TNF-α, IFN-γ, IL-2, IL-4, and IL-6. We provide a detailed time course for the expression of these cytokines, both in liver and plasma. Cytokine neutralization revealed that, unlike Con A-induced hepatitis, IFN-γ is not only dispensable for α-GalCer-induced hepatotoxicity but even appears to exert protective effects. In contrast, TNF-α was clearly identified as an important mediator for hepatic injury in this model that increased Fas ligand expression on NKT cells. Whereas intrahepatic Kupffer cells are known as a pivotal source for TNF-α in Con A-induced hepatitis, they were nonessential for α-GalCer-mediated hepatotoxicity. In α-GalCer-treated mice, TNF-α was produced by intrahepatic lymphocytes, in particular NKT cells. BALB/c mice were significantly less susceptible to α-GalCer-induced liver injury than C57BL/6 mice, in particular upon pretreatment with d-galactosamine, a hepatocyte-specific sensitizer to TNF-α-mediated injury. Finally, we demonstrate resemblance of murine α-GalCer-induced hepatitis to human autoimmune-like liver disorders. The particular features of this model compared with other immune-mediated hepatitis models may enhance comprehension of basic mechanisms in the etiopathogenesis of NKT cell-comprising liver disorders.

Tim‐3 blockade promotes iNKT cell function to inhibit HBV replication

“…FCM data showed that 2 μg of α‐Galcer largely decreased both the per cent and number of hepatic iNKT cells within 24 hours (Figure 2A,B) which were consistent with previous report 12. Comparing with non‐α‐Galcer group, α‐Galcer strikingly increased the expression of IFN‐γ, TNF‐α, IL‐4 and CD107a in iNKT cells (Figure 2C,D).…”

“…Specially, iNKT cells are CD1d‐restricted and can be activated by α‐Galcer, a glycolipid from marine sponge 7, 8. iNKT cells, on activation, can produce both Th1 cytokines such as IFN‐γ and Th2 cytokines such as IL‐4/IL‐13 within a few hours, the intensity and magnitude of which are closely related to various disease outcome such as cancer and infection 9, 10, 11, 12. Increasing evidence suggests that iNKT cells play a key role in anti‐HBV immunity 13, 14, 15.…”

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

“…5G). TNF-α released by hepatic iNKT cells plays an important role in liver damage following α-GalCer administration (26,27). Hepatic iNKT cells isolated from Raptor eKO mice produced lower levels of TNF-α than WT controls (Fig.…”

“…We further investigated the pathophysiological relevance of impaired iNKT-cell function in Raptor-deficient mice using a model of α-GalCer-induced hepatitis (26,27). Seventeen hours after α-GalCer injection, serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), markers of liver damage, were considerably elevated in WT mice.…”

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…In the context of sterile inflammation, iNKT cells can have deleterious effects on local and systemic responses. For example, iNKT cells strongly participate in hepatitis induced by concanavalin A 54,68 and ␣-GalCer, 69,70 in hepatic reperfusion injury, 71,72 and in lipopolysaccharide-induced 73 or cecal ligation and puncture-mediated 74 acute septic shock. We evaluated their potential regulatory function in DENV-induced disease.…”