An increased MRP8/14 expression and adhesion, but a decreased migration towards proinflammatory chemokines of type 1 diabetes monocytes
An increased MRP8/14 expression and adhesion, but a decreased migration towards proinflammatory chemokines of type 1 diabetes monocytes
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DOI：
10.1111/j.1365-2249.2005.02865.x
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发表时间：
2005-09-01
影响因子：
4.6
通讯作者：
Versnel, MA
中科院分区：
文献类型：
--
作者：
Bouma, G;Coppens, JMC;Versnel, MA
在1型糖尿病的早期发展过程中，巨噬细胞和树突状细胞在纤连蛋白表达部位的胰岛周围聚集。人们认为这些巨噬细胞和树突状细胞来源于血液单核细胞。此前，我们发现1型糖尿病患者血清中MRP8/14水平升高，这会诱导健康的单核细胞更强地黏附于纤连蛋白（FN）。在此我们表明，1型糖尿病患者的单核细胞会更高水平地表达和产生MRP8/14，尤其是在黏附于FN之后，从而为高纤连蛋白黏附能力创造了一个正反馈机制。1型糖尿病患者的单核细胞对内皮细胞的黏附也增加了。尽管黏附增加，但1型糖尿病患者的单核细胞向促炎趋化因子CCL2和CCL3的跨内皮迁移却减少了。由于非肥胖糖尿病（NOD）小鼠的单核细胞也表现出类似的促炎迁移缺陷，我们认为单核细胞向促炎趋化因子迁移受损可能是自身免疫性糖尿病的一个特征。这种单核细胞对促炎趋化因子反应受阻的情况，让人质疑糖尿病胰腺中早期巨噬细胞和树突状细胞的聚集是否源于炎症驱动的单核细胞流入。我们还表明，1型糖尿病患者的单核细胞向与淋巴组织相关的CCL19的迁移增加，并且与单核细胞表面CCR7表达增加相关。由于NOD小鼠在早期胰腺中这些与淋巴组织相关的趋化因子高表达，所以糖尿病胰腺中早期巨噬细胞和树突状细胞的聚集更有可能与胰腺中与淋巴组织相关的趋化因子异常高表达有关。
In the early development of type 1 diabetes macrophages and dendritic cells accumulate around the islets of Langerhans at sites of fibronectin expression. It is thought that these macrophages and dendritic cells are derived from blood monocytes. Previously, we showed an increased serum level of MRP8/14 in type 1 diabetes patients that induced healthy monocytes to adhere more strongly to fibronectin (FN). Here we show that MRP8/14 is expressed and produced at a higher level by type 1 diabetes monocytes, particularly after adhesion to FN, creating a positive feedback mechanism for a high fibronectin-adhesive capacity. Also adhesion to endothelial cells was increased in type 1 diabetes monocytes. Despite this increased adhesion the transendothelial migration of monocytes of type 1 diabetes patients was decreased towards the proinflammatory chemokines CCL2 and CCL3. Because non-obese diabetic (NOD) mouse monocytes show a similar defective proinflammatory migration, we argue that an impaired monocyte migration towards proinflammatory chemokines might be a hallmark of autoimmune diabetes. This hampered monocyte response to proinflammatory chemokines questions whether the early macrophage and dendritic cell accumulation in the diabetic pancreas originates from an inflammatory-driven influx of monocytes. We also show that the migration of type 1 diabetes monocytes towards the lymphoid tissue-related CCL19 was increased and correlated with an increased CCR7 surface expression on the monocytes. Because NOD mice show a high expression of these lymphoid tissue-related chemokines in the early pancreas it is more likely that the early macrophage and dendritic cell accumulation in the diabetic pancreas is related to an aberrant high expression of lymphoid tissue-related chemokines in the pancreas.