Matrix Metalloproteinase-9 Signaling Regulates Colon Barrier Integrity in Models of HIV Infection.

Michael Ohene-Nyako, Amanda L Persons, Christopher Forsyth, Ali Keshavarzian, T Celeste Napier
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Abstract

Infection with human immunodeficiency virus (HIV) increases risk for maladies of the gut barrier, which promotes sustained systemic inflammation even in virally controlled patients. We previously revealed morphological disorganization of colon epithelial barrier proteins in HIV-1 transgenic (Tg) rats. The current study evaluated mechanisms that may underlie gut barrier pathology induced by toxic HIV-1 proteins. Methamphetamine (meth) use is prevalent among HIV-infected individuals, and meth can exaggerate morbidity of HIV infection. Thus, we determined whether meth exposure worsened HIV-associated gut pathology using colon samples from HIV-1 Tg and non-Tg rats that self-administered meth 2 h/day for 21 days. Immunoblotting was conducted for occludin (a gut barrier protein) and matrix metalloproteinase-9 (MMP-9; a proteinase regulator of occludin). Colon levels of occludin were decreased, and MMP-9 levels and activity were increased in HIV-1 Tg rats. A Pearson correlation revealed an inverse relationship between occludin levels and MMP-9 activity. Doses of meth that were self-administered by Tg rats were lower than other rat models. Meth-induced trends in non-Tg rats were not significant, and meth did not exaggerate effects seen in Tg rats. Accordingly, only the HIV-effects on epithelial function were explored further. Transepithelial resistance (TER) across a monolayer of human colon epithelial cells (Caco-2) was used to examine treatments with the HIV-1 toxic protein, Tat, and the ability of pioglitazone, a PPARγ agonist that inhibits MMP-9, to mitigate Tat-induced changes. Exposure to Tat for 24 h decreased TER, which co-occurred with decreases in levels of barrier tight junction proteins (occludin, claudin-1, and zonula occludens-1) and with increases in the level and activity of MMP-9. Pretreatment or post-treatment with pioglitazone respectively prevented and restored Tat-induced impairments of Caco-2 barrier. Thus, while low doses of meth did not alter barrier proteins in the current study, exposure to HIV-1 proteins disrupted the gut barrier, and this action involved a dysregulation of MMP-9.

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基质金属蛋白酶-9 信号调节艾滋病毒感染模型中结肠屏障的完整性
感染人类免疫缺陷病毒(HIV)会增加肠道屏障畸形的风险,即使在病毒得到控制的患者中也会引发持续的全身性炎症。我们之前发现,HIV-1 转基因(Tg)大鼠的结肠上皮屏障蛋白形态紊乱。本研究评估了毒性 HIV-1 蛋白诱导肠道屏障病变的机制。甲基苯丙胺(冰毒)的使用在 HIV 感染者中很普遍,冰毒会加重 HIV 感染的发病率。因此,我们使用 HIV-1 Tg 大鼠和非 Tg 大鼠的结肠样本,测定甲基苯丙胺暴露是否会加重 HIV 相关的肠道病理。对闭塞素(一种肠道屏障蛋白)和基质金属蛋白酶-9(MMP-9,闭塞素的蛋白酶调节剂)进行了免疫印迹分析。HIV-1 Tg 大鼠结肠中的闭塞素水平降低,MMP-9 的水平和活性升高。皮尔逊相关性显示,闭塞素水平与 MMP-9 活性之间存在反比关系。Tg 大鼠自行服用的甲基安非他明剂量低于其他大鼠模型。冰毒在非 Tg 大鼠中的诱导趋势并不明显,冰毒也没有夸大 Tg 大鼠的影响。因此,我们只进一步探讨了艾滋病毒对上皮功能的影响。研究人员使用单层人结肠上皮细胞(Caco-2)的跨上皮阻力(TER)来检测 HIV-1 毒性蛋白 Tat 的处理情况,以及吡格列酮--一种抑制 MMP-9 的 PPARγ 激动剂--缓解 Tat 诱导的变化的能力。暴露于 Tat 24 小时会降低 TER,同时屏障紧密连接蛋白(occludin、claudin-1 和 zonula occludens-1)的水平也会降低,MMP-9 的水平和活性也会增加。用吡格列酮进行预处理或后处理可分别防止和恢复 Tat 诱导的 Caco-2 屏障损伤。因此,在当前的研究中,虽然低剂量的冰毒不会改变屏障蛋白,但暴露于 HIV-1 蛋白会破坏肠道屏障,这种作用涉及 MMP-9 的失调。
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