Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
Department of Dental Oncology & Maxillofacial Prosthetics, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2C1, Canada.
J Cell Sci. 2020 Dec 23;133(24):jcs248864. doi: 10.1242/jcs.248864.
Multinucleated giant cells (MGCs) are prominent in foreign body granulomas, infectious and inflammatory processes, and auto-immune, neoplastic and genetic disorders, but the molecular determinants that specify the formation and function of these cells are not defined. Here, using tandem mass tag-mass spectrometry, we identified a differentially upregulated protein, C-type lectin domain family 10 member (herein denoted CD301, also known as CLEC10A), that was strongly upregulated in mouse RAW264.7 macrophages and primary murine macrophages undergoing interleukin (IL-4)-induced MGC formation. CD301 MGCs were identified in biopsy specimens of human inflammatory lesions. Function-inhibiting CD301 antibodies or CRISPR/Cas9 deletion of the two mouse CD301 genes (Mgl1 and Mgl2) inhibited IL-4-induced binding of N-acetylgalactosamine-coated beads by 4-fold and reduced MGC formation by 2.3-fold (<0.05). IL-4-driven fusion and MGC formation were restored by re-expression of CD301 in the knockout cells. We conclude that in monocytes, IL-4 increases CD301 expression, which mediates intercellular adhesion and fusion processes that are required for the formation of MGCs.This article has an associated First Person interview with the first author of the paper.
多核巨细胞（MGCs）在外来体肉芽肿、感染和炎症过程以及自身免疫、肿瘤和遗传疾病中很明显，但指定这些细胞形成和功能的分子决定因素尚不清楚。在这里，我们使用串联质量标签-质谱法鉴定了一种差异上调的蛋白质，C 型凝集素结构域家族 10 成员（在此表示为 CD301，也称为 CLEC10A），它在小鼠 RAW264.7 巨噬细胞和经白细胞介素（IL-4）诱导形成 MGC 的原代小鼠巨噬细胞中强烈上调。在人类炎症病变的活检标本中鉴定出 CD301 MGCs。功能抑制 CD301 抗体或 CRISPR/Cas9 敲除两种小鼠 CD301 基因（Mgl1 和 Mgl2）将 IL-4 诱导的 N-乙酰半乳糖胺包被珠的结合抑制 4 倍，并将 MGC 形成减少 2.3 倍（<0.05）。在敲除细胞中重新表达 CD301 可恢复 IL-4 驱动的融合和 MGC 形成。我们得出结论，在单核细胞中，IL-4 增加 CD301 的表达，这介导了细胞间粘附和融合过程，这些过程是形成 MGCs 所必需的。本文附有该论文第一作者的第一人称采访。
