Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
J Neuroimmune Pharmacol. 2020 Jun;15(2):280-291. doi: 10.1007/s11481-019-09887-6. Epub 2019 Dec 20.
Histamine is a major peripheral inflammatory mediator and a neurotransmitter in the central nervous system. We have reported that histamine induces microglia activation and releases proinflammatory factors in primary cultured microglia. Whether histamine has similar effects in vivo is unknown. In the present study, we aimed to investigate the role of histamine and its receptors in the release of inflammatory mediators and activation of microglia in rat brain. We site-directed injected histamine, histamine receptor agonists or histamine receptor antagonists in the rat lateral ventricle using stereotaxic techniques. Flow cytometry was employed to determine histamine receptor expression in rat microglia. Microglia activation was assessed by Iba1 immunohistochemistry. The levels of tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and interleukin-10 (IL-10) were measured with commercial enzyme-linked immunosorbent assay (ELISA) kits, TNF-α, IL-1β and IL-10 mRNA expressions were determined with Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). We found that all four types of histamine receptors were expressed in rat brain microglia. Histamine was able to induce microglia activation and subsequent production of the inflammatory factors TNF-α, IL-1β and IL-10, and these effects were partially abolished by HR and HR antagonists. However, HR and HR antagonists significantly increased production of TNF-α and IL-1β, and decreased IL-10 levels. The HR or HR agonists stimulated the production of TNF-α and IL-1β, while the HR or HR agonists increased IL-10 release. Our results demonstrate that histamine induces microglia activation and the release of both proinflammatory and anti-inflammatory factors in rat brain, thus contributing to the development of inflammation in the brain. Graphical Abstract Histamine induces microglia activation and the release of both proinflammatory (TNF-α and IL-1β) and anti-inflammatory factors (IL-10) in rat brain, thus contributing to the development of inflammation in the brain.
组胺是外周炎症介质和中枢神经系统中的神经递质。我们已经报道，组胺在原代培养的小胶质细胞中诱导小胶质细胞活化并释放促炎因子。组胺在体内是否具有类似的作用尚不清楚。在本研究中，我们旨在研究组胺及其受体在大鼠脑内炎症介质释放和小胶质细胞活化中的作用。我们使用立体定向技术将组胺、组胺受体激动剂或组胺受体拮抗剂直接注射到大鼠侧脑室。采用流式细胞术测定大鼠小胶质细胞中组胺受体的表达。通过 Iba1 免疫组化评估小胶质细胞的活化。采用商业酶联免疫吸附试验（ELISA）试剂盒测定肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-10（IL-10）的水平，采用定量实时聚合酶链反应（qRT-PCR）测定 TNF-α、IL-1β 和 IL-10 的 mRNA 表达。我们发现，四种类型的组胺受体均在大鼠脑小胶质细胞中表达。组胺能够诱导小胶质细胞活化，随后产生促炎因子 TNF-α、IL-1β 和 IL-10，这些作用部分被 HR 和 HR 拮抗剂所阻断。然而，HR 和 HR 拮抗剂显著增加了 TNF-α 和 IL-1β 的产生，降低了 IL-10 的水平。HR 或 HR 激动剂刺激 TNF-α 和 IL-1β 的产生，而 HR 或 HR 激动剂增加了 IL-10 的释放。我们的结果表明，组胺在大鼠脑中诱导小胶质细胞活化和促炎及抗炎因子的释放，从而促进脑内炎症的发展。
图摘要 组胺在大鼠脑中诱导小胶质细胞活化和促炎（TNF-α和 IL-1β）及抗炎因子（IL-10）的释放，从而促进脑内炎症的发展。
