Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock.
Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock.
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DOI：
10.1371/journal.pone.0009593
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发表时间：
2010-03-09
期刊：
影响因子：
3.7
通讯作者：
Wang CY
中科院分区：
文献类型：
--
作者：
Zhong J;Yang P;Muta K;Dong R;Marrero M;Gong F;Wang CY
鉴于Jak2在细胞信号传导中的重要性，Jak2在免疫细胞特别是树突状细胞（DCs）中的关键作用早已被提出。然而，Jak2在dc中的确切功能仍然知之甚少，因为Jak2缺乏会导致胚胎死亡。本研究通过他莫昔芬诱导，建立了成年Cre+/+Jak2fl/fl小鼠Jak2缺乏症。Jak2的缺失显著损害了DC的发展，表现为BMDC产量降低、脾脏大小减小和DC在总脾细胞中的百分比降低。Jak2对于dc介导先天免疫反应的能力也至关重要。Jak2−/−dc对炎症刺激的反应能力较弱，并且显示出分泌促炎细胞因子如TNFα和IL-12的能力降低。结果，Jak2−/−小鼠在感染后对李斯特菌的早期清除存在缺陷。然而，它们介导适应性免疫反应的效力不受影响。与dc不同，Jak2−/−巨噬细胞显示出相似的促炎细胞因子分泌能力，表明Jak2以dc依赖的方式选择性调节先天免疫反应。与这些结果一致，Jak2−/−小鼠对lps诱导的致死剂量脓毒性休克（一种以过度先天免疫反应为特征的致命脓毒症）具有显著的抗性，并且正常dc的过继转移恢复了它们对lps诱导的脓毒性休克的易感性。机制研究表明，Jak2/SATA5信号通路是DC发育和成熟的关键，而DC分泌促炎细胞因子的能力受Jak2/STAT5和Jak2/STAT6信号通路的调节。
Given the importance of Jak2 in cell signaling, a critical role for Jak2 in immune cells especially dendritic cells (DCs) has long been proposed. The exact function for Jak2 in DCs, however, remained poorly understood as Jak2 deficiency leads to embryonic lethality. Here we established Jak2 deficiency in adult Cre+/+Jak2fl/fl mice by tamoxifen induction. Loss of Jak2 significantly impaired DC development as manifested by reduced BMDC yield, smaller spleen size and reduced percentage of DCs in total splenocytes. Jak2 was also crucial for the capacity of DCs to mediate innate immune response. Jak2−/− DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFα and IL-12. As a result, Jak2−/− mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak2−/− macrophages showed similar capacity secretion of proinflammatory cytokines, suggesting that Jak2 selectively modulates innate immune response in a DC-dependent manner. Consistent with these results, Jak2−/− mice were remarkably resistant to lethal dose of LPS-induced septic shock, a deadly sepsis characterized by the excessive innate immune response, and adoptive transfer of normal DCs restored their susceptibility to LPS-induced septic shock. Mechanistic studies revealed that Jak2/SATA5 signaling is pivotal for DC development and maturation, while the capacity for DCs secretion of proinflammatory cytokines is regulated by both Jak2/STAT5 and Jak2/STAT6 signaling.
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影响因子：
15.3
作者：
Carter, L L;Murphy, K M
通讯作者：
Murphy, K M
DOI：
10.1084/jem.175.6.1531
发表时间：
1992-06-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Bevan MJ
影响因子：
4.4
作者：
Granucci, F;Feau, S;Ricciardi-Castagnoli, P
通讯作者：
Ricciardi-Castagnoli, P
影响因子：
4.4
作者：
Chiang, PH;Wang, LF;Qian, SG
通讯作者：
Qian, SG
影响因子：
168.9
作者：
Laffort, C;Le Deist, F;Fischer, A
通讯作者：
Fischer, A