Amelioration of Murine Macrophage Activation Syndrome by Monomethyl Fumarate in Both a Heme Oxygenase 1-Dependent and Heme Oxygenase 1-Independent Manner.
Amelioration of Murine Macrophage Activation Syndrome by Monomethyl Fumarate in Both a Heme Oxygenase 1-Dependent and Heme Oxygenase 1-Independent Manner.
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DOI：
10.1002/art.41591
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Behrens EM
中科院分区：
文献类型：
--
作者：
Biswas C;Chu N;Burn TN;Kreiger PA;Behrens EM
巨噬细胞激活综合征(MAS)表现为血清铁蛋白和血红素加氧酶-1(HO-1)升高，但这些分子在MAS中的功能尚不清楚。由于HO-1具有抗炎作用，我们推测HO-1的药理活性可以改善MAS的疾病活动性。富马酸二甲酯(DMF)是FDA批准的治疗多发性硬化症的药物，它激活HO-1。富马酸单甲酯(MMF)是DMF的活性代谢物。因此，我们在小鼠MAS模型中评估了MMF是否可以诱导HO-1依赖的治疗改进。我们通过重复激活TLR9在野生型和髓系特异性HO-1缺陷小鼠中诱导了MAS。每天服用两次MMF以测试其疗效。我们评估了器官重量、血清细胞因子、组织组织学和完整的血细胞计数以评估疾病活动性。使用学生T检验或双因素方差分析进行适当的统计检验。TLR9诱导的IL-10大部分需要HO-1。IL-10在TLR9-MAS小鼠中的产生与髓系HO-1基因剂量相关(p<；0.001)。MMF治疗使脾巨噬细胞中的HO-1增加了约2倍(p<；0.01)。霉酚酸酯治疗以HO-1依赖的方式升高TLR9-MAS患者的血清IL-10(p<；0.005)，并以HO-1依赖和非依赖的方式改善多种疾病参数。TLR9诱导的IL-10在体内外均受HO-1活性控制。在小鼠模型中，HO-1/IL-10轴的治疗性增强能够显著改善MAS疾病的活动性。这些结果表明，靶向HO-1作为MAS的治疗靶点可能是可行的，在MAS治疗的研究中应考虑DMF和MMF。
Macrophage activation syndrome (MAS) demonstrates increased serum ferritin and heme-oxygenase 1 (HO-1), yet no known function is ascribed to these molecules in MAS. Because HO-1 is anti-inflammatory we hypothesized that pharmacologic activation of HO-1 could ameliorate MAS disease activity. Dimethylfumarate (DMF), an FDA-approved treatment for multiple sclerosis, activates HO-1. Monomethylfumarate (MmF) is the active metabolite of DMF. We therefore evaluated whether MmF could elicit HO-1-dependent therapeutic improvements in a murine-MAS model. We induced MAS by repeated activation of TLR9 in wild type and myeloid specific HO-1-deficient mice. MmF was administered twice daily to test its efficacy. We assessed organ weights, serum cytokines, tissue histology, and complete blood counts to evaluate disease activity. Statistical testing as appropriate was performed using Student’s T-test or by 2-way ANOVA. HO-1 is required for the majority of TLR9 induced IL-10. IL-10 production in TLR9-MAS-mice correlates with the myeloid-HO-1 gene dose (p < 0.001). MmF treatment increased HO-1 in splenic macrophages approximately 2-fold (p <0.01). MmF therapy increased serum IL-10 in an HO-1- dependent manner in TLR9-MAS (p < 0.005), and improved multiple disease parameters in both HO-1- dependent and -independent manners. TLR9 induced IL-10 is under the control of HO-1 activity both in vitro and in vivo. Therapeutic enhancement of the HO-1/IL-10 axis in a murine model was able to significantly ameliorate MAS disease activity. These results suggest targeting HO-1 may be viable as a MAS therapeutic target, and DMF and MmF should be considered in investigations of MAS therapy.
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影响因子：
7.3
作者：
Ng TH;Britton GJ;Hill EV;Verhagen J;Burton BR;Wraith DC
通讯作者：
Wraith DC
DOI：
10.1007/s00018-016-2223-0
发表时间：
2016-09
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Loboda A;Damulewicz M;Pyza E;Jozkowicz A;Dulak J
通讯作者：
Dulak J
影响因子：
20.3
作者：
Girard-Guyonvarc'h, Charlotte;Palomo, Jennifer;Gabay, Cem
通讯作者：
Gabay, Cem
影响因子：
4.8
作者：
Biswas, Chhanda;Shah, Nidhi;Dennery, Phyllis A.
通讯作者：
Dennery, Phyllis A.
嗜血型巨噬细胞构成败血症中血红素氧酶表达的主要区室。
影响因子：
3.1
作者：
Schaer, Dominik J;Schaer, Christian A;Schoedon, Gabriele;Imhof, Alexander;Kurrer, Michael O
通讯作者：
Kurrer, Michael O