Bae Heekyong R, Shin Su-Kyung, Lee Ji-Yoon, Ko Yeo Jin, Kim Suntae, Young Howard A, Kwon Eun-Young
Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea.
Center for Food and Nutritional Genomics, Kyungpook National University, Daegu 41566, Republic of Korea.
Int J Mol Sci. 2024 Dec 25;26(1):63. doi: 10.3390/ijms26010063.
Mitochondrial dysfunction and macrophage dysregulation are well recognized as significant contributors to the pathogenesis of autoimmune diseases. However, the detailed mechanisms connecting these two factors remain poorly understood. This study hypothesizes that low but chronic interferon-gamma (IFN-γ) plays a critical role in these processes. To explore this, we utilized ARE-Del mice, a model characterized by sustained low-level IFN-γ expression and lupus nephritis (LN)-like symptoms. Age- and tissue-dependent gene expression analyses in ARE-Del mice revealed significant suppression of mitochondrial complex I components and activities, particularly in the kidneys. The genotype-dependent suppression of mitochondrial complex I indicates early disruption, which leads to macrophage dysfunction. Notably, remission restored gene expression of mitochondrial complex I and macrophage dysfunction in isolated renal macrophages from NZB/W lupus-prone mice. These findings suggest that chronic low-level IFN-γ disrupts mitochondrial complex I activity in macrophages, highlighting its role in the early pathogenesis of autoimmune diseases like lupus nephritis. This provides new insights into the molecular interactions underlying autoimmune pathogenesis and suggests potential targets for therapeutic intervention.
线粒体功能障碍和巨噬细胞失调被公认为是自身免疫性疾病发病机制的重要促成因素。然而，连接这两个因素的详细机制仍知之甚少。本研究假设，低水平但持续的干扰素-γ（IFN-γ）在这些过程中起关键作用。为了探究这一点，我们利用了ARE-Del小鼠，这是一种以持续低水平IFN-γ表达和狼疮性肾炎（LN）样症状为特征的模型。对ARE-Del小鼠进行的年龄和组织依赖性基因表达分析显示，线粒体复合体I的成分和活性受到显著抑制，尤其是在肾脏中。线粒体复合体I的基因型依赖性抑制表明早期破坏，这会导致巨噬细胞功能障碍。值得注意的是，缓解恢复了NZB/W狼疮易感小鼠分离的肾巨噬细胞中线粒体复合体I的基因表达和巨噬细胞功能障碍。这些发现表明，慢性低水平IFN-γ会破坏巨噬细胞中线粒体复合体I的活性，突出了其在狼疮性肾炎等自身免疫性疾病早期发病机制中的作用。这为自身免疫发病机制背后的分子相互作用提供了新的见解，并提示了治疗干预的潜在靶点。
