Yaniv Salem, Niva Yacov, Pinhas Kafri, Oshrat Propheta-Meiran, Arnon Karni, Nitsan Maharshak, Victoria Furer, Ori Elkayam, Itzhak Mendel
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Data show that silencing of MOSPD2 expression in the THP-1 monocytic cell line significantly increased cell adhesion to various ECM molecules. Employing IW-601, a humanized anti-human MOSDP2 monoclonal antibody, on primary human monocytes increased adhesion to ECM molecules as well as to adhesion molecules. At the molecular level, silencing of MOSPD2 or blocking MOSPD2 using IW-601 led to a transition in integrin αLβ2 (CD11a/CD18, LFA-1) conformation into an active high-affinity binding form and to the induction of adhesion-associated signaling pathways. Co-immunoprecipitation experiments showed that MOSPD2 binds integrin-β2 (CD18), but not integrin-β1 (CD29). Our results reveal a novel mechanism controlling monocyte migration, in which MOSPD2 acts as an adhesion checkpoint that governs the balance between monocyte adhesion and release. 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引用次数: 0
摘要
单核细胞是先天免疫细胞,驱动各种炎症性疾病的慢性。单核细胞向炎症组织的迁移涉及与血管内皮和细胞外基质(ECM)相互作用的多个步骤,这一过程是通过细胞表面整合素的构象转变介导的。我们之前描述过,运动精子结构域蛋白2 (MOSPD2)是骨髓细胞表达的一种表面蛋白,对单核细胞的迁移和炎症的关键调节至关重要。为了研究MOSPD2的作用机制,我们评估了它是否在调节整合素激活和单核细胞粘附中起作用。数据显示,沉默THP-1单核细胞系中MOSPD2的表达可显著增加细胞对各种ECM分子的粘附。使用人源化抗人MOSDP2单克隆抗体IW-601,在原代人单核细胞上增加对ECM分子和粘附分子的粘附。在分子水平上,沉默MOSPD2或使用IW-601阻断MOSPD2可导致整合素α - l β2 (CD11a/CD18, LFA-1)构象转变为活跃的高亲和力结合形式,并诱导粘附相关的信号通路。共免疫沉淀实验表明,MOSPD2与整合素-β2 (CD18)结合,而不与整合素-β1 (CD29)结合。我们的研究结果揭示了一种控制单核细胞迁移的新机制,其中MOSPD2作为一个粘附检查点,控制单核细胞粘附和释放之间的平衡。通过证明IW-601对慢性炎症性疾病患者分离的原代单核细胞迁移的抑制作用,我们为将MOSPD2的机制转化为炎症性疾病的潜在治疗提供了概念证明,进一步得到RA和IBD模型的体内数据的支持。
MOSPD2 regulates the activation state of αLβ2 integrin to control monocyte migration: applicability for treatment of chronic inflammatory diseases.
Monocytes are innate immune cells that drive the chronicity of various inflammatory diseases. Monocyte migration to inflamed tissues involves multiple steps of interaction with the vascular endothelium and the extracellular matrix (ECM), a process mediated through conformational transitions in cell surface integrins. We previously described motile sperm domain-containing protein 2 (MOSPD2) as a surface protein expressed on myeloid cells that is essential for the migration of monocytes and a key regulator of inflammation. Investigating MOSPD2's mechanism of action, we assessed whether it plays a role in regulating integrin activation and monocyte adhesion. Data show that silencing of MOSPD2 expression in the THP-1 monocytic cell line significantly increased cell adhesion to various ECM molecules. Employing IW-601, a humanized anti-human MOSDP2 monoclonal antibody, on primary human monocytes increased adhesion to ECM molecules as well as to adhesion molecules. At the molecular level, silencing of MOSPD2 or blocking MOSPD2 using IW-601 led to a transition in integrin αLβ2 (CD11a/CD18, LFA-1) conformation into an active high-affinity binding form and to the induction of adhesion-associated signaling pathways. Co-immunoprecipitation experiments showed that MOSPD2 binds integrin-β2 (CD18), but not integrin-β1 (CD29). Our results reveal a novel mechanism controlling monocyte migration, in which MOSPD2 acts as an adhesion checkpoint that governs the balance between monocyte adhesion and release. By demonstrating the inhibitory effect of IW-601 on the migration of primary monocytes isolated from patients with chronic inflammatory diseases, we provide proof of concept for translating MOSPD2's mechanism into a potential treatment for inflammatory diseases, further supported by in vivo data in models of RA and IBD.
期刊介绍:
IMMUNOLOGIC RESEARCH represents a unique medium for the presentation, interpretation, and clarification of complex scientific data. Information is presented in the form of interpretive synthesis reviews, original research articles, symposia, editorials, and theoretical essays. The scope of coverage extends to cellular immunology, immunogenetics, molecular and structural immunology, immunoregulation and autoimmunity, immunopathology, tumor immunology, host defense and microbial immunity, including viral immunology, immunohematology, mucosal immunity, complement, transplantation immunology, clinical immunology, neuroimmunology, immunoendocrinology, immunotoxicology, translational immunology, and history of immunology.