Yu Qijun, Mei Hong, Gu Qian, Zeng Ran, Li Yanan, Zhang Junjie, Gao Chenxu, Fang Hai, Qu Jieming, Liu Jia
Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai 200025, China.
Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Int J Biol Sci. 2025 Feb 26;21(5):2275-2295. doi: 10.7150/ijbs.103859. eCollection 2025.
Olfactomedin-like protein 3 (OLFML3), belonging to olfactomedin (OLF) protein family, has poorly defined functions. Recent studies have reported the functions of OLFML3 in anti-viral immunity and tumorigenesis. In this study, we investigated the roles of OLFML3 in macrophages. In LPS- or -induced acute lung injury (ALI) mouse model, OLFML3 depletion exacerbated inflammatory response, leading to reduced survival. OLFML3 achieved the activity by regulating macrophage phagocytosis and migration. Mass spectrometry analysis revealed immunoresponsive gene 1 (IRG1) as an OLFML3-interacting protein. IRG1 is a mitochondrial decarboxylase that catalyzes the conversion of -aconitate to itaconate, a myeloid-borne mitochondrial metabolite with immunomodulatory activities. Further investigation showed that OLFML3 could prevent LPS-induced mitochondrial dysfunction in macrophages by maintaining the homeostasis of mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS) and itaconate-related metabolites. In-depth protein-protein interaction studies showed that OLFML3 could promote IRG1 mitochondrial localization via a mitochondrial transport protein, apoptosis inducing factor mitochondria associated 1 (AIFM1). In summary, our study showed that OLFML3 could facilitate IRG1 mitochondrial localization and prevent LPS-induced mitochondrial dysfunction in macrophages.
嗅觉介质样蛋白3（OLFML3）属于嗅觉介质（OLF）蛋白家族，其功能尚不明确。最近的研究报道了OLFML3在抗病毒免疫和肿瘤发生中的作用。在本研究中，我们研究了OLFML3在巨噬细胞中的作用。在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠模型中，OLFML3缺失加剧了炎症反应，导致存活率降低。OLFML3通过调节巨噬细胞的吞噬作用和迁移来发挥活性。质谱分析显示免疫反应基因1（IRG1）是一种与OLFML3相互作用的蛋白。IRG1是一种线粒体脱羧酶，可催化顺乌头酸转化为衣康酸，衣康酸是一种具有免疫调节活性的髓源性线粒体代谢产物。进一步研究表明，OLFML3可通过维持线粒体膜电位（MMP）、线粒体活性氧（mtROS）和衣康酸相关代谢产物的稳态，预防LPS诱导的巨噬细胞线粒体功能障碍。深入的蛋白质-蛋白质相互作用研究表明，OLFML3可通过线粒体转运蛋白凋亡诱导因子线粒体相关1（AIFM1）促进IRG1在线粒体中的定位。总之，我们的研究表明，OLFML3可促进IRG1在线粒体中的定位，并预防LPS诱导的巨噬细胞线粒体功能障碍。
