Abstract：
We previously demonstrated that mice carrying natural mtDNA variants of the FVB/NJ strain (m.7778 G>T in the mt-Atp8 gene in mitochondrial complex V), namely C57BL/6 J-mtFVB/NJ (B6-mtFVB), exhibited (i) partial protection from experimental skin inflammatory diseases in an anti-murine type VII collagen antibody-induced skin inflammation model and psoriasiform dermatitis model; (ii) significantly altered metabolites, including short-chain fatty acids, according to targeted metabolomics of liver, skin and lymph node samples; and (iii) a differential composition of the gut microbiota according to bacterial 16 S rRNA gene sequencing of stool samples compared to wild-type C57BL/6 J (B6) mice. To further dissect these disease-contributing factors, we induced an experimental antibody-induced skin inflammatory disease in gnotobiotic mice. We performed shotgun metagenomic sequencing of caecum contents and untargeted metabolomics of liver, CD4+ T cell, and caecum content samples from conventional B6-mtFVB and B6 mice. We identified D-glucosamine as a candidate mediator that ameliorated disease severity in experimental antibody-induced skin inflammation by modulating immune cell function in T cells, neutrophils and macrophages. Because mice carrying mtDNA variants of the FVB/NJ strain show differential disease susceptibility to a wide range of experimental diseases, including diet-induced atherosclerosis in low-density lipoprotein receptor knockout mice and collagen antibody-induced arthritis in DBA/1 J mice, this experimental approach is valuable for identifying novel therapeutic options for skin inflammatory conditions and other chronic inflammatory diseases to which mice carrying specific mtDNA variants show differential susceptibility.
摘要：
我们先前证明了携带FVB/NJ菌株的天然mtDNA变体的小鼠（线粒体复合物V中mt-Atp8基因中的m.7778G>T），即C57BL/6J-MTFVB/NJ（B6-MTFVB），在抗鼠VII型胶原抗体诱导的皮肤炎症模型和银屑病样皮炎模型中表现出（i）对实验性皮肤炎性疾病的部分保护；（ii）代谢产物显着改变，包括短链脂肪酸,根据肝脏的靶向代谢组学，皮肤和淋巴结样品;和(iii)与野生型C57BL/6J(B6)小鼠相比,根据粪便样品的细菌16SrRNA基因测序的肠道微生物群的差异组成。为了进一步剖析这些致病因素，我们诱导了实验性抗体诱导的皮肤炎症性疾病的小鼠。我们进行了盲肠内容物的鸟枪宏基因组测序和肝脏的非靶向代谢组学，CD4+T细胞,和来自常规B6-mtFVB和B6小鼠的盲肠含量样品。我们确定D-葡糖胺是通过调节T细胞中的免疫细胞功能来改善实验性抗体诱导的皮肤炎症中疾病严重程度的候选介质。中性粒细胞和巨噬细胞。因为携带FVB/NJ株mtDNA变异体的小鼠对多种实验性疾病表现出不同的疾病易感性,包括饮食诱导的低密度脂蛋白受体敲除小鼠的动脉粥样硬化和胶原抗体诱导的DBA/1J小鼠的关节炎，这种实验方法对于确定针对皮肤炎症性疾病和其他慢性炎症性疾病的新型治疗选择是有价值的,这些小鼠对携带特定mtDNA变体的小鼠表现出不同的易感性.
