TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury
TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury
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DOI：
10.4049/jimmunol.1501609
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Dimitra Vyrla;G. Nikolaidis;F. Oakley;M. Perugorria;P. Tsichlis;D. Mann;A. Eliopoulos
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文献类型：
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作者：
Dimitra Vyrla;G. Nikolaidis;F. Oakley;M. Perugorria;P. Tsichlis;D. Mann;A. Eliopoulos
不变NKT(INKT)细胞代表先天T淋巴细胞的一个亚群，其功能是作为支持肝损伤的肝脏炎症的协调者。在这项研究中，我们证明了Tpl2是CD3+NK1.1+iNKT细胞中的一个信号因子和肝脏炎症的介质，它是一种主要被认为是巨噬细胞反应中的MAP3激酶。Tpl2基因消融可改善ConA诱导的小鼠肝损伤，并影响肝脏NKT细胞激活的标志，而不影响胸腺NKT细胞的发育。使用iNKT特异性配体α-半乳糖神经酰胺的研究进一步证实了Tpl2在iNKT细胞功能中的关键作用，该研究以Tpl2依赖的方式导致小鼠轻度肝炎，包括产生效应细胞因子IL-4和干扰素-γ，中性粒细胞的聚集，以及肝脏中其他免疫细胞类型的许可和激活。一种Tpl2激酶抑制剂在体内反映了Tpl2基因消融的效果，发现ERK和Akt是Tpl2调控的信号通路，通过激活转录因子JunB和Nfat负责IL-4和干扰素-γ的表达。总之，这些发现扩大了我们对iNKT细胞激活机制的理解，并表明Tpl2的调节有可能将免疫驱动的肝病的严重程度降至最低。
Invariant NKT (iNKT) cells represent a subset of innate-like T lymphocytes that function as orchestrators of hepatic inflammation underpinning liver damage. In this study, we demonstrate that TPL2, an MAP3 kinase that has mostly been appreciated for its physiological role in macrophage responses, is a signaling factor in CD3+NK1.1+ iNKT cells and mediator of hepatic inflammation. Genetic ablation of TPL2 in the mouse ameliorates liver injury induced by Con A and impinges on hallmarks of NKT cell activation in the liver without affecting NKT cell development in the thymus. The pivotal role of TPL2 in iNKT cell functions is further endorsed by studies using the iNKT-specific ligand α-galactosylceramide, which causes mild hepatitis in the mouse in a TPL2-dependent manner, including production of the effector cytokines IL-4 and IFN-γ, accumulation of neutrophils and licensing and activation of other immune cell types in the liver. A TPL2 kinase inhibitor mirrors the effects of genetic ablation of TPL2 in vivo and uncovers ERK and Akt as the TPL2-regulated signaling pathways responsible for IL-4 and IFN-γ expression through the activation of the transcription factors JunB and NFAT. Collectively, these findings expand our understanding of the mechanisms of iNKT cell activation and suggest that modulation of TPL2 has the potential to minimize the severity of immune-driven liver diseases.