Dysregulated heme oxygenase-1(low) M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons.
Dysregulated heme oxygenase-1(low) M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons.
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DOI：
10.1186/s13075-018-1568-1
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发表时间：
2018-04-10
影响因子：
4.9
通讯作者：
Nakajima H
中科院分区：
文献类型：
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作者：
Kishimoto D;Kirino Y;Tamura M;Takeno M;Kunishita Y;Takase-Minegishi K;Nakano H;Kato I;Nagahama K;Yoshimi R;Igarashi K;Aoki I;Nakajima H
巨噬细胞（macrophages，M β）等天然免疫在狼疮性肾炎（lupus nephritis，LN）中的作用日益受到重视，但M β在LN中的作用尚不明确。免疫组化染色检测LN患者肾小球中CD 68、CD 163、血红素加氧酶（HO）-1（一种具有抗炎特性的应激诱导血红素降解酶）、pSTAT 1和表达CMAF的M β。通过RT-PCR和免疫细胞染色评估I型干扰素对人M2样M表达CD 163、HO-1、BTB和CNC homology 1（Bach 1;转录HO-1抑制剂）、白细胞介素（IL）-6和IL-10水平的影响，这些M是用巨噬细胞集落刺激因子从外周单核细胞中体外分化出来的。在Bach 1缺陷型和野生型MRL/lpr小鼠中比较临床表现、抗双链DNA（抗dsDNA）和局部HO-1表达。LN患者肾小球M2样M β的数量与尿蛋白量相关。与单核细胞来源的M2样M β不同，HO-1在LN患者的大多数肾小球M2样M β中表达缺陷。用I型干扰素刺激人M2样M β导致HO-1表达减少，Bach 1和IL-6表达增加。Bach 1缺陷型MRL/lpr小鼠肾脏HO-1表达增加，生存期延长，尿蛋白减少，血清尿素氮水平降低，但血清抗dsDNA抗体水平相当。Bach 1缺陷型MRL/lpr小鼠腹腔巨噬细胞中CD 163和HO-1的表达增加。我们的数据表明，失调的M2样M β在LN中起促炎作用。Bach 1是一个潜在的治疗靶点，可以恢复M2 M β的抗炎特性。本文的在线版本（10.1186/s13075-018-1568-1）包含补充材料，可供授权用户使用。
Innate immunity including macrophages (Mϕ) in lupus nephritis (LN) has been gaining attention, but roles of Mϕ in LN remain uncertain. Immunohistochemical staining was performed to determine CD68, CD163, heme oxygenase (HO)-1 (a stress-inducible heme-degrading enzyme with anti-inflammatory property), pSTAT1, and CMAF-expressing Mϕ in the glomeruli of patients with LN. Effects of type I interferons on the expression levels of CD163, HO-1, BTB and CNC homology 1 (Bach1; a transcriptional HO-1 repressor), interleukin (IL)-6, and IL-10 by human M2-like Mϕ, which were differentiated in vitro from peripheral monocytes with macrophage colony-stimulating factor, were assessed by RT-PCR and immunocytostaining. Clinical manifestations, anti-double-stranded DNA (anti-dsDNA), and local HO-1 expression were compared in Bach1-deficient and wild-type MRL/lpr mice. The number of glomerular M2-like Mϕ correlated with the amounts of proteinuria in patients with LN. Unlike monocyte-derived M2-like Mϕ, HO-1 expression was defective in the majority of glomerular M2-like Mϕ of patients with LN. Stimulation of human M2-like Mϕ with type I interferons led to reduced HO-1 expression and increased Bach1 and IL-6 expression. Bach1-deficient MRL/lpr mice exhibited increased HO-1 expression in kidneys, prolonged survival, reduced urine proteins, and serum blood urea nitrogen levels, but serum anti-dsDNA antibody levels were comparable. Increased expression of CD163 and HO-1 was found in peritoneal Mϕ from Bach1-deficient MRL/lpr mice. Our data suggest that dysregulated M2-like Mϕ play a proinflammatory role in LN. Bach1 is a potential therapeutic target that could restore the anti-inflammatory property of M2 Mϕ. The online version of this article (10.1186/s13075-018-1568-1) contains supplementary material, which is available to authorized users.
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