Cardiovascular Biology and Inflammation Research Group, Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK.
Nutr Metab Cardiovasc Dis. 2011 Nov;21(11):871-8. doi: 10.1016/j.numecd.2010.02.019. Epub 2010 Jul 31.
Atherosclerosis is known to be an inflammatory disease and there is increasing evidence that chylomicron remnants (CMR), the lipoproteins which carry dietary fats in the blood, cause macrophage foam cell formation and inflammation. In early atherosclerosis the frequency of activated monocytes in the peripheral circulation is increased, and clearance of CMR from blood may be delayed, however, whether CMR contribute directly to monocyte activation and subsequent egress into the arterial wall has not been established. Here, the contribution of CMR to activation of monocyte pro-inflammatory pathways was assessed using an in vitro model.
Primary human monocytes and CMR-like particles (CRLP) were used to measure several endpoints of monocyte activation. Treatment with CRLP caused rapid and prolonged generation of reactive oxygen species by monocytes. The pro-inflammatory chemokines MCP-1 and IL-8 were secreted in nanogram quantities by the cells in the absence of CRLP. IL-8 secretion was transiently increased after CRLP treatment, and CRLP maintained secretion in the presence of pharmacological inhibitors of IL-8 production. In contrast, exposure to CRLP significantly reduced MCP-1 secretion. Chemotaxis towards MCP-1 was increased in monocytes pre-exposed to CRLP and was reversed by addition of exogenous MCP-1.
Our findings indicate that CRLP activate human monocytes and augment their migration in vitro by reducing cellular MCP-1 expression. Our data support the current hypothesis that CMR contribute to the inflammatory milieu of the arterial wall in early atherosclerosis, and suggest that this may reflect direct interaction with circulating blood monocytes.
动脉粥样硬化是一种炎症性疾病，越来越多的证据表明，乳糜微粒残粒（CMR），即血液中携带膳食脂肪的脂蛋白，会导致巨噬细胞泡沫细胞的形成和炎症。在动脉粥样硬化早期，外周循环中活化的单核细胞频率增加，而 CMR 从血液中的清除可能会延迟，但是 CMR 是否直接导致单核细胞活化以及随后进入动脉壁尚未确定。在这里，使用体外模型评估了 CMR 对单核细胞促炎途径的激活作用。
使用原代人单核细胞和 CMR 样颗粒（CRLP）来测量单核细胞活化的几个终点。CRLP 处理可使单核细胞快速且持续地产生活性氧。在没有 CRLP 的情况下，细胞以纳克数量分泌促炎趋化因子 MCP-1 和 IL-8。CRLP 处理后，IL-8 分泌短暂增加，并且 CRLP 在 IL-8 产生的药理学抑制剂存在的情况下维持分泌。相反，暴露于 CRLP 会显著减少 MCP-1 的分泌。预先用 CRLP 处理的单核细胞对 MCP-1 的趋化性增加，并且通过添加外源性 MCP-1 可以逆转。
我们的发现表明，CRLP 通过减少细胞内 MCP-1 的表达来激活人单核细胞并增强其体外迁移。我们的数据支持当前的假设，即 CMR 有助于动脉粥样硬化早期动脉壁的炎症环境，并表明这可能反映了与循环血液单核细胞的直接相互作用。
