Zhu Wenhua, Lönnblom Erik, Förster Michael, Johannesson Martina, Tao Pei, Meng Liesu, Lu Shemin, Holmdahl Rikard
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 710061 Xi'an, China.
Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, 710061 Xi'an, China.
Sci Adv. 2020 Oct 21;6(43). doi: 10.1126/sciadv.aba9337. Print 2020 Oct.
We have positionally cloned the gene, with a duplication and a promoter polymorphism, as a major regulator of inflammation. Mice with the RIIIS/J haplotype, with the absence of Ym1 expression, showed reduced susceptibility to mannan-enhanced collagen antibody-induced arthritis and to chronic arthritis induced by intranasal exposure of mannan. Depletion of lung macrophages alleviated arthritis, whereas intranasal supplement of Ym1 protein to -deficient mice reversed the disease, suggesting a key role of Ym1 for inflammatory activity by lung macrophages. -deficient mice with pneumonitis had less eosinophil infiltration, reduced production of type II cytokines and IgG1, and skewing of macrophages toward alternative activation due to enhanced STAT6 activation. Proteomics analysis connected Ym1 polymorphism with changed lipid metabolism. Induced PPAR-γ and lipid metabolism in -deficient macrophages contributed to cellular polarization. In conclusion, the natural polymorphism of Ym1 regulates alternative activation of macrophages associated with pulmonary inflammation.
我们已经定位克隆了该基因，它存在重复和启动子多态性，是炎症的主要调节因子。具有RIIIS/J单倍型且缺乏Ym1表达的小鼠，对甘露聚糖增强的胶原抗体诱导的关节炎以及经鼻暴露于甘露聚糖诱导的慢性关节炎的易感性降低。肺巨噬细胞的耗竭减轻了关节炎，而向缺乏Ym1的小鼠经鼻补充Ym1蛋白可逆转疾病，这表明Ym1在肺巨噬细胞的炎症活动中起关键作用。患有肺炎的缺乏Ym1的小鼠嗜酸性粒细胞浸润较少，II型细胞因子和IgG1的产生减少，并且由于STAT6激活增强，巨噬细胞向替代性活化倾斜。蛋白质组学分析将Ym1多态性与脂质代谢改变联系起来。在缺乏Ym1的巨噬细胞中诱导的PPAR-γ和脂质代谢有助于细胞极化。总之，Ym 的自然多态性调节与肺部炎症相关的巨噬细胞的替代性活化。
