Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Neuropsychiatry, Kumamoto University Faculty of Life Sciences, Kumamoto, Japan.
PLoS One. 2022 Mar 24;17(3):e0265738. doi: 10.1371/journal.pone.0265738. eCollection 2022.
Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter.
We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain.
SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes.
These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.
巨噬细胞移动抑制因子（MIF）是一种多功能细胞因子，可促进神经发生和神经保护。MIF 主要在大脑中的星形胶质细胞中表达。已知血清 MIF 水平和 MIF 基因启动子区域的微卫星/单核苷酸多态性（SNP）与精神分裂症（SCZ）有关。有趣的是，先前的研究报道，缺氧是 SCZ 的环境危险因素，通过缺氧诱导因子（HIF）-1与 MIF 启动子中的缺氧反应元件（HRE）结合来诱导 MIF 表达。
我们研究了 MIF 在 SCZ 中的作用，重点关注 HIF 途径。首先，我们在 1758 例 SCZ 患者和 1507 例对照中进行了 MIF 启动子中 HRE 的 SNP rs17004038（C>A）的关联研究。接下来，我们研究了缺氧对源自新生小鼠前脑的原代培养星形胶质细胞中 MIF 表达的影响。
SNP rs17004038 与 SCZ 显著相关（p = 0.0424，优势比= 1.445），表明 MIF 启动子 HRE 中的该 SNP 是 SCZ 的遗传危险因素。缺氧诱导 MIF mRNA 表达和 MIF 蛋白产生，并增加 HIF-1 与 MIF 启动子的结合，而 HRE 突变和星形胶质细胞中 HRE 缺失抑制 MIF 启动子的活性。
这些结果表明，MIF 启动子 HRE 中的 SNP rs17004038 与 SCZ 显著相关，并且可能通过抑制缺氧和 HIF 途径诱导的 MIF 表达参与 SCZ 的病理生理学。
