Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain
Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain
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DOI：
10.1016/j.redox.2020.101684
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Matalon, Sadis
中科院分区：
文献类型：
--
作者：
Aggarwal, Saurabh;DeBerry, Jennifer J.;Matalon, Sadis
慢性广泛性疼痛（CWP）在艾滋病毒感染者中的患病率很高，但其潜在机制尚不清楚。白细胞在其内质网（ER）内合成内源性阿片样物质8-内啡肽。当释放到血浆中时，8-内啡肽通过与感觉神经元上的阿片受体结合来抑制伤害感受。我们假设血红素依赖的氧化还原信号诱导ER应激，其减弱白细胞8-内啡肽水平/释放，从而增加HIV患者的疼痛敏感性。结果表明，HIV阳性个体与CWP增加血浆高铁血红蛋白，红细胞膜氧化，溶血，和低血浆血红素清除酶，血红素结合蛋白，与HIV无CWP和HIV阴性个体有或无疼痛的人相比。此外，患有CWP的HIV患者的白细胞中血红素代谢酶血红素加氧酶-1的水平降低，血红素加氧酶-1将游离血红素代谢为一氧化碳和胆绿素。这些个体还具有升高的ER应激和白细胞中的低8-内啡肽。在体外，血红素暴露或血红素加氧酶-1缺失，减少小鼠单核细胞/巨噬细胞中的8-内啡肽。用一氧化碳供体或ER应激抑制剂处理细胞，增加8-内啡肽。为了模拟临床前模型中的溶血作用，向C57 BL/6小鼠注射盐酸苯肼（PHZ）。PHZ增加细胞游离血红素和ER应激，降低白细胞8-内啡肽水平和后爪机械敏感性阈值。用血红素结合素治疗PHZ注射小鼠阻断了这些作用，表明血红素诱导的ER应激和随后的白细胞8-内啡肽减少是HIV感染者超敏反应的原因。
The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, 8-endorphin, within their endoplasmic reticulum (ER). When released into plasma, 8-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte 8-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low 8-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased 8-endorphins in murine monocytes/ macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased 8-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte 8-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte 8-endorphin is responsible for hypersensitivity in people with HIV.