Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury.
Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury.
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DOI：
10.4049/jimmunol.1601948
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发表时间：
2017-05-01
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影响因子：
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通讯作者：
Dhandapani KM
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作者：
Braun M;Vaibhav K;Saad N;Fatima S;Brann DW;Vender JR;Wang LP;Hoda MN;Baban B;Dhandapani KM
创伤性脑损伤（TBI）是一个重大的公共卫生问题，造成严重的患者死亡率和不良的长期预后。越来越多的证据表明，免疫系统在脑外伤后数天和数周内继发性神经损伤的发展中扮演着重要的角色，但尚未明确。在此，我们验证了外周巨噬细胞浸润在脑损伤后启动持久适应性免疫反应的假设。使用小鼠控制的皮质冲击模型，我们使用过继转移、转基因和骨髓嵌合体方法来显示巨噬细胞浸润和促炎（M1）极化在tbi后长达三周的时间内增加。在混合淋巴细胞反应中，从损伤脑中纯化的单核细胞刺激naïve T淋巴细胞的增殖，增强T效应细胞（Teff: TH1/TH17）的极化，减少调节性T细胞（TREG）的产生。同样，在TBI后，血液和脑组织中升高的Teff极化通过髓细胞耗竭而减弱。功能上，与C3H/OuJ（野生型）小鼠相比，C3H/HeJ （TLR4突变体）小鼠在TBI后逆转了M1巨噬细胞和TH1/TH17极化。此外，与C3H/OuJ单核细胞相比，从C3H/HeJ小鼠分离的脑单核细胞对T淋巴细胞增殖和TH1/TH17极化的刺激作用较弱。综上所述，我们的数据表明tlr4依赖性M1巨噬细胞转运/极化进入中枢神经系统是急性TBI和长期适应性免疫反应之间的关键机制联系。
Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurological injury over the days and weeks following a TBI. Herein, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and pro-inflammatory (M1) polarization of macrophages for up to three weeks post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naïve T lymphocytes, enhanced the polarization of T effector cells (Teff: TH1/TH17), and decreased the production of regulatory T cells (TREG) in a mixed lymphocyte reaction. Similarly, elevated Teff polarization within both blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed both M1 macrophage and TH1/TH17 polarization after TBI, as compared to C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and TH1/TH17 polarization, as compared to C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses.