Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection.
Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection.
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DOI：
10.1016/j.bbi.2020.06.016
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Kaul M
中科院分区：
文献类型：
--
作者：
Ojeda-Juárez D;Shah R;Fields JA;Harahap-Carrillo IS;Koury J;Maung R;Gelman BB;Baaten BJ;Roberts AJ;Kaul M
尽管进行了联合抗逆转录病毒治疗，艾滋病毒感染者 (PLWH) 仍继续出现与艾滋病毒相关的神经认知障碍。 Lipocalin-2 (LCN2) 是一种急性期蛋白，与神经变性有关，并且在 HIV 相关脑损伤的转基因小鼠模型中表达上调。在这里，我们发现，在患有大脑病理学的 HIV 感染者亚群的新皮质中，LCN2 显着上调，并且与脑脊液中的病毒载量和新皮质中的前病毒 DNA 相关。然而，LCN2 是否会导致 HIV 相关的神经毒性，或者是宿主保护性反应的一部分，这一问题还需要进一步研究。我们发现，在大脑中表达 HIVgp120 (HIVgp120tg) 的转基因小鼠中敲除 LCN2 可消除行为障碍，改善神经元损伤，并减少与神经保护性 CCR5 配体 CCL4 增加相关的小胶质细胞活化。体外实验表明，LCN2 神经毒性还取决于小胶质细胞和 p38 MAPK 活性。 LCN2缺陷型HIVgp120tg小鼠中CCR5的基因消除可恢复神经病理学，表明LCN2超越CCR5及其趋化因子配体介导的神经保护作用。参与神经传递的 168 个基因的 RNA 表达表明，神经元损伤和保护均与影响常见神经基因网络的基因型和性别特异性模式相关。总之，我们的研究确定 LCN2 是 HIV 相关脑损伤的一个新因素，涉及 CCR5、p38 MAPK 和小胶质细胞。此外，LCN2和CCR5之间的机制相互作用可以作为有脑病理学和神经认知障碍风险的HIV患者的诊断和治疗靶点。
People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmission reveals that neuronal injury and protection are each associated with genotype- and sex-specific patterns affecting common neural gene networks. In conclusion, our study identifies LCN2 as a novel factor in HIV-associated brain injury involving CCR5, p38 MAPK and microglia. Furthermore, the mechanistic interaction between LCN2 and CCR5 may serve as a diagnostic and therapeutic target in HIV patients at risk of developing brain pathology and neurocognitive impairment.
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影响因子：
3.2
作者：
Fields, Jerel;Dumaop, Wilmar;Rockenstein, Edward;Mante, Michael;Spencer, Brian;Grant, Igor;Ellis, Ron;Letendre, Scott;Patrick, Christina;Adame, Anthony;Masliah, Eliezer
通讯作者：
Masliah, Eliezer
影响因子：
56.9
作者：
COCCHI, F;DEVICO, AL;LUSSO, P
通讯作者：
LUSSO, P
影响因子：
5.3
作者：
Hoefer, Melanie M.;Sanchez, Ana B.;Maung, Ricky;de Rozieres, Cyrus M.;Catalan, Irene C.;Dowling, Cari C.;Thaney, Victoria E.;Pina-Crespo, Juan;Zhang, Dongxian;Roberts, Amanda J.;Kaul, Marcus
通讯作者：
Kaul, Marcus
影响因子：
11
作者：
Kang SS;Ren Y;Liu CC;Kurti A;Baker KE;Bu G;Asmann Y;Fryer JD
通讯作者：
Fryer JD
DOI：
10.1037/h0077579
发表时间：
1979-01-01
期刊：
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
影响因子：
--
作者：
BARNES, CA
通讯作者：
BARNES, CA