GWAS-identified CCR1 and IL10 loci contribute to M1 macrophage-predominant inflammation in Behçet's disease.
GWAS-identified CCR1 and IL10 loci contribute to M1 macrophage-predominant inflammation in Behçet's disease.
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DOI：
10.1186/s13075-018-1613-0
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发表时间：
2018-06-12
影响因子：
4.9
通讯作者：
Nakajima H
中科院分区：
文献类型：
--
作者：
Nakano H;Kirino Y;Takeno M;Higashitani K;Nagai H;Yoshimi R;Yamaguchi Y;Kato I;Aoki I;Nakajima H
C-C趋化因子受体1（CCR 1）和白细胞介素（IL）-10的低表达与白塞病（BD）的风险相关。本研究的目的是澄清先前的BD全基因组关联研究（GWASs）确定的CCR 1和IL 10位点的病理作用。用粒细胞-巨噬细胞集落刺激因子或巨噬细胞集落刺激因子（M-CSF）从健康对照受试者（HC）和BD患者的外周血单核细胞中分化出M1和M2巨噬细胞（Mφ）。检测CD 68和CD 163的表达以检测Mφ极化。根据CCR 1和IL-10单核苷酸多态性（SNP）基因型比较CCR 1和IL-10信使RNA（mRNA）和蛋白表达。比较M1和M2 Mφ向CCR 1配体巨噬细胞炎性蛋白（MIP）-1α的迁移能力。比较了BD和系统性硬化症（SSc）皮损中M1和M2 Mφ的比例，后者被报道为M2 Mφ占优势。为了研究极化Mφ的可塑性，将分化的细胞在相同或不同的培养条件下培养。与M1 Mφ相比，M2 Mφ中CD 163、CCR 1和IL-10的表达明显增强。M2 Mφ较M1 Mφ对低浓度MIP-1α迁移更敏感。BD来源的M1 Mφ比HC来源的M1 Mφ显示更高的CCR 1表面表达。通过GWAS鉴定的SNP基因型观察极化Mφ中IL 10和CCR 1 mRNA表达的差异。与SSc皮损相比，BD皮损显示M1 Mφ优势。可塑性试验显示M-CSF恢复M1 Mφ的IL-10合成并减少IL-6的产生。本研究揭示了GWAS鉴定的SNP有助于BD中M1 Mφ主导的炎症。我们的数据还表明，偏斜的Mφ极化是可以通过免疫干预来纠正的。本文的在线版本（10.1186/s13075-018-1613-0）包含补充材料，可供授权用户使用。
Low C-C chemokine receptor 1 (CCR1) and interleukin (IL)-10 expression is associated with risk of Behçet’s disease (BD). The objective of the present study was to clarify the pathological roles of CCR1 and IL10 loci identified by previous BD genome-wide association studies (GWASs). M1 and M2 macrophages (Mφ) were differentiated with granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor (M-CSF) from peripheral monocytes of healthy control subjects (HC) and patients with BD. Expression of CD68 and CD163 was evaluated to test for Mφ polarization. CCR1 and IL-10 messenger RNA (mRNA) and protein expression was compared according to CCR1 and IL10 single-nucleotide polymorphism (SNP) genotypes. The migratory ability of M1 and M2 Mφ toward CCR1 ligand macrophage inflammatory protein (MIP)-1α was compared. The ratio of M1 and M2 Mφ in skin lesions of BD and systemic sclerosis (SSc), which was reported to be M2 Mφ-dominant, was compared. To examine the plasticity of polarized Mφ, the differentiated cells were cultured with either the same or the other culture condition. Preferential expression of CD163, CCR1, and IL-10 was found in M2 Mφ compared with M1 Mφ. M2 Mφ migrated more sensitively to low concentrations of MIP-1α than M1 Mφ did. BD-derived M1 Mφ showed higher CCR1 surface expression than HC-derived M1 Mφ did. IL10 and CCR1 mRNA expression differences were observed by GWAS-identified SNP genotypes in polarized Mφ. BD skin lesions showed M1 Mφ predominance compared with SSc skin lesions. A plasticity assay revealed that M-CSF restored IL-10 synthesis and reduced IL-6 production by M1 Mφ. The present study reveals that GWAS-identified SNPs contribute to M1 Mφ-predominant inflammation in BD. Our data also suggest that the skewed Mφ polarization is correctable by immunological intervention. The online version of this article (10.1186/s13075-018-1613-0) contains supplementary material, which is available to authorized users.
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