T-Cell Immunoglobulin Mucin-3 Determines Severity of Liver Ischemia/Reperfusion Injury in Mice in a TLR4-Dependent Manner

Abstract

The newly discovered T-cell immunoglobulin mucin (TIM) gene family molecules, expressed by T cells, regulate host immunity and tolerance. Although CD4+ T cells mediate innate immunity-dominated liver ischemia-reperfusion injury (IRI), the underlying mechanisms remain obscure. We have recently documented the novel function of TIM-1 pathway in the mechanism of liver IRI and also found that TLR4 activation plays a key triggering role. Using an anti-TIM-3 Ab, we now studied the role of TIM-3 signaling in the model of partial warm liver ischemia followed by reperfusion. Anti-TIM-3 Ab therapy exacerbated the liver damage, as compared with controls. Histological examination has revealed that anti-TIM-3 Ab augmented the hepatocellular damage, increased local neutrophil infiltration, facilitated local accumulation of T cells/macrophages and promoted liver cell apoptosis. Intrahepatic neutrophil activity, induction of pro-inflammatory cytokines/chemokines and expression of cleaved caspase-3/NF-NB/TLR4 were all increased in the treatment group. In parallel, anti-TIM-3 Ab and anti-galectin-9 (Gal-9; TIM-3 ligand) Ab increased IFN-γ production in ConA-stimulated spleen T cells, and TNFα/IL-6 expression in ConA-stimulated macrophage/T cell co-culture system. Interestingly, anti-TIM-3 Ab treatment did not affect liver IRI in TLR4-deficient (KO) mice. In conclusion, TIM-3 blockade exacerbated local inflammation and liver damage, suggesting importance of TIM-3/Gal-9 signaling in the maintenance of hepatic homeostasis. TIM-3-TLR4 cross regulation determined the severity of liver IRI in TLR4-dependent manner, a novel finding of potential importance to modulate tissue innate vs. adaptive responses in liver transplant patients. Thus, harnessing physiological negative T cell co-stimulation signaling on hepatic T cells may minimize innate immunity-mediated liver tissue damage.

Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

“…Consistent with previous studies (12,20) wt mice undergoing 90 min of warm partial IRI featured signs (increased ALT and hepatocellular necrosis) of hepatic injury 24 h after reperfusion (data not shown). Gr-1-immunohistochemistry (IHC) and MPO results showed massive infiltration of neutrophils in the necrotic liver areas (data not shown).…”

The Innate Immune System and Transplantation

“…The induction of proinflammatory cytokine and chemokine programs was also blunted, data supported by findings from a renal I/R injury mouse model (Rong et al 2011). The TIM-3 -Gal-9, on the other hand, constitutes a "negative" T-cell costimulation signal, as TIM-3 blockade worsens tissue damage, along with increased IFN-g and reciprocally depressed IL-10 expression in I/Rstressed organs (Uchida et al 2010b). The PD-1 (B7)-PD-L1 (H1) "negative" T-cell pathway has been also shown to promote I/R cytoprotection (Ji et al 2010;Ueki et al 2011).…”

T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response

“…For example, data show that Tim-3 controls the extent of the inflammatory response by suppressing the TLR4 response (24,25). However, the underlying mechanisms remain largely unclear.…”

“…However, the underlying mechanisms remain largely unclear. Because sepsis is characterized by immune disorders in which an uncontrolled TLR response plays a major pathogenic role (2,4,26) and because the Tim-3 pathway is actively involved in homeostatic immune regulation and may play a negative regulatory role in the TLR-mediated response (24,25), it is important to know whether the Tim-3 pathway is also involved in the regulation of sepsis, and, if so, whether it plays a negative regulatory role.…”