The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human.
The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human.
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作者：
Korpos É;Kadri N;Kappelhoff R;Wegner J;Overall CM;Weber E;Holmberg D;Cardell S;Sorokin L
我们首次全面分析了 NOD 小鼠 1 型糖尿病和人类 1 型糖尿病发展过程中胰岛周围胶囊的细胞外基质 (ECM) 组成，该胶囊由胰岛周围基底膜 (BM) 和下方的间质基质 (IM) 组成。我们的数据表明，仅在白细胞浸润到胰岛的部位，胰岛周围 BM 和 IM 成分的整体损失。体视学分析揭示了胰岛炎的发生率与显示胰岛周围 BM 丢失的胰岛数量与具有完整 BM 的胰岛之间的相关性，表明白细胞渗透到胰岛周围 BM 是关键步骤。对激光解剖白细胞浸润和非浸润胰岛进行蛋白酶和蛋白酶抑制剂特异性微阵列分析 (CLIP-CHIP)，并进行定量实时 PCR 和蛋白质分析，确定了胰岛周围 BM 白细胞渗透部位的组织蛋白酶 S、W 和 C 活性与巨噬细胞亚群相关 在 NOD 小鼠和人类 1 型糖尿病样本中，因此可能是专门作用于胰岛渗透阶段的新治疗靶点。有趣的是，一旦炎症消退，胰岛周围的 BM 和底层的 IM 就会重建，这表明胰岛周围的 BM 生成细胞不会因炎症而丢失，这对胰岛移植研究具有重要影响。
We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step. Protease- and protease inhibitor–specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies.
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