Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.
Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.
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DOI：
10.1007/s00401-023-02627-4
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发表时间：
2023-11
影响因子：
12.7
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中科院分区：
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在多发性硬化症(MS)中，慢性病变边缘的铁敏感磁共振成像(MRI)可以显示持续的炎症活动。这些顺磁性边缘病变(PRL)与临床恶化有关，尽管铁摄取和代谢的细胞类型特异性和分子途径尚不清楚。我们研究了两个死后队列：18名对照组和24名MS患者的探索性福尔马林固定石蜡包埋(FFPE)组织队列，以及6名对照组和14名MS患者的验证性快速冷冻队列。除髓鞘和非血红素铁显像外，结合珠蛋白-血红蛋白清道夫受体CD163、铁代谢标记物Hmox1和HAMP以及免疫相关标记物P2RY12、CD68、C1QA和IL10在不同MS病变区的髓系细胞(MC)亚型中均可见。此外，我们通过铁敏感的3T磁共振成像和结合珠蛋白基因分型，对98例多发性硬化(PWMS)患者体内的PRL进行了研究。采集38例PWMS患者的脑脊液标本，用酶联免疫吸附试验检测可溶性CD163(SCD163)蛋白水平。在死后组织中，我们观察到铁摄取与RIM相关的C1QA表达MC亚型有关，其特征是CD163、Hmox1、HAMP上调，反之，P2RY12下调。发现有4个PRL的PWMS的脑脊液中sCD163水平高于有3个PRL的PWMS，且sCD163与PRL的数量相关。PRL的数量与PWMS的临床恶化有关，但与年龄、性别或结合珠蛋白基因无关。然而，具有HP2-1/HP2-2单倍型的PWMS的临床残疾评分高于具有HP1-1的PWMS。综上所述，我们观察到慢性活动性病变边缘MC亚型的CD163-Hmox1-HAMP轴上调，这表明结合珠蛋白结合的血红蛋白而不是转铁蛋白结合的铁是多发性硬化患者MC相关铁摄取的关键来源。脑脊液相关的sCD163与多发性硬化症的PRL计数的相关性强调了CD163通过结合珠蛋白结合的血红蛋白介导的铁摄取的相关性。此外，虽然HP单倍型对PRL计数没有明显影响，但携带HP2等位基因的PWMS携带者可能有更高的临床恶化风险。网上版载有补充材料，可在10.1007/s00401-023-023-4查阅。
In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with 4 PRLs had higher sCD163 levels in the CSF than pwMS with 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening. The online version contains supplementary material available at 10.1007/s00401-023-02627-4.