Heme-Induced Macrophage Phenotype Switching and Impaired Endogenous Opioid Homeostasis Correlate with Chronic Widespread Pain in HIV.
Heme-Induced Macrophage Phenotype Switching and Impaired Endogenous Opioid Homeostasis Correlate with Chronic Widespread Pain in HIV.
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DOI：
10.3390/cells12121565
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发表时间：
2023-06-06
期刊：
影响因子：
6
通讯作者：
Aggarwal, Saurabh
中科院分区：
文献类型：
--
作者：
Chatterjee, Tanima;Arora, Itika;Underwood, Lilly B.;Lewis, Terry L.;Juncos, Juan Xavier Masjoan;Heath, Sonya L.;Goodin, Burel R.;Aggarwal, Saurabh
慢性广泛性疼痛（CWP）与HIV-1（PWH）患者的高残疾率和生活质量下降有关。我们以前的研究表明，PWH与CWP有增加的溶血和升高的血浆水平的无细胞血红素，这与低内源性阿片样物质水平的白细胞。此外，我们证明了无细胞血红素损害β-内啡肽从白细胞的合成/释放。然而，血红素抑制β-内啡肽产生的细胞机制尚不确定。目前的假设是血红素依赖性TLR 4激活和巨噬细胞极化M1表型介导这种现象。我们的新发现表明，PWH与CWP具有升高的M1特异性巨噬细胞趋化因子（ENA-78，GRO-α和IP-10）在血浆中。在体外，通过用TLR 4抑制剂TAK-242处理细胞，可减轻血红素诱导的M0和M2巨噬细胞极化为具有低β-内啡肽的M1表型。类似地，在体内将溶血诱导剂盐酸苯肼（PHZ）注射到C57 B1/6小鼠中增加了M1/M2细胞比率并降低了β-内啡肽水平。然而，用血红素清除蛋白血红素结合蛋白（Hx）或TAK-242给药这些动物可降低M1/M2比值并增加β-内啡肽。此外，Hx可减弱血红素诱导的机械、热和冷超敏反应，而TAK-242可消除对机械和热刺激的超敏反应。总的来说，这些结果表明，血红素介导的TLR 4激活和M1极化的巨噬细胞与受损的内源性阿片类药物的稳态和超敏反应的人与艾滋病毒。
Chronic widespread pain (CWP) is associated with a high rate of disability and decreased quality of life in people with HIV-1 (PWH). We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs β-endorphin synthesis/release from leukocytes. However, the cellular mechanisms by which heme dampens β-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-α, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low β-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl/6 mice increased the M1/M2 cell ratio and reduced β-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1/M2 ratio and increased β-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV.
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