Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain.
Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain.
复制标题
JNK1 失活可增强先天性 IL-10 的产生并抑制大脑中的自身免疫炎症。
DOI：
10.1073/pnas.0601155103
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发表时间：
2006
影响因子：
11.1
通讯作者：
Flavell,RichardA
中科院分区：
文献类型：
--
作者：
Tran,EliseH;Azuma,Yasu-Taka;Chen,Manchuan;Weston,Claire;Davis,RogerJ;Flavell,RichardA
微生物病原体等环境损伤可导致自身反应性T细胞活化，导致靶器官炎症，最终导致自身免疫性疾病。各种感染与多发性硬化症及其动物对应物自身免疫性脑脊髓炎有关。先天免疫触发自身反应性的分子过程目前还不清楚。通过使用多发性硬化症的小鼠模型，我们发现MAPK，c-Jun N-末端激酶1（JNK 1）的遗传缺失增强了IL-10的产生，使先天性骨髓细胞对某些微生物无反应，并且产生IL-17的能力较低，致脑炎性T细胞。此外，JNK 1缺陷型中枢神经系统骨髓细胞不能对效应T细胞炎性细胞因子作出反应，从而阻止进一步进展为神经炎症。因此，我们已经确定骨髓细胞中的JNK 1信号转导途径是自身免疫性疾病中介导炎症反应的调节回路的关键组成部分。我们的研究结果提供了进一步的见解的关键MAPK调节网络的先天性和适应性细胞因子的进展，以自身免疫。
Environmental insults such as microbial pathogens can contribute to the activation of autoreactive T cells, leading to inflammation of target organs and, ultimately, autoimmune disease. Various infections have been linked to multiple sclerosis and its animal counterpart, autoimmune encephalomyelitis. The molecular process by which innate immunity triggers autoreactivity is not currently understood. By using a mouse model of multiple sclerosis, we found that the genetic loss of the MAPK, c-Jun N-terminal kinase 1 (JNK1), enhances IL-10 production, rendering innate myeloid cells unresponsive to certain microbes and less capable of generating IL-17–producing, encephalitogenic T cells. Moreover, JNK1-deficient central nervous system myeloid cells are unable to respond to effector T cell inflammatory cytokines, preventing further progression to neuroinflammation. Thus, we have identified the JNK1 signal transduction pathway in myeloid cells to be a critical component of a regulatory circuit mediating inflammatory responses in autoimmune disease. Our findings provide further insights into the pivotal MAPK-regulated network of innate and adaptive cytokines in the progression to autoimmunity.