The Discipline of Pathology, School of Medical Sciences, Bosch Institute, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
Sci Transl Med. 2014 Jan 15;6(219):219ra7. doi: 10.1126/scitranslmed.3007563.
Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate-induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.
炎性单核细胞衍生效应细胞在许多炎症性疾病的发病机制中起着重要作用。然而，目前还没有能够特异性调节这些细胞的治疗方法。我们发现，从聚苯乙烯、微金刚石或可生物降解的聚（乳酸-共-羟基乙酸）衍生的带负电荷的免疫调节微粒（IMPs），通过巨噬细胞胶原结构受体（MARCO），以非调理素依赖的方式被炎性单核细胞摄取。随后，这些单核细胞不再迁移到炎症部位；相反，通过凋亡细胞清除机制，IMP 输注将其隔离在脾脏中，并最终通过半胱天冬酶-3 介导的细胞凋亡。在心肌梗死、实验性自身免疫性脑脊髓炎、葡聚糖硫酸钠诱导的结肠炎、巯基乙酸诱导的腹膜炎和致死性黄病毒脑炎的小鼠模型中，给予 IMPs 可显著减少炎症灶处的单核细胞聚集，减轻疾病症状，并促进组织修复。总之，这些数据强调了清道夫受体、脾脏和炎性单核细胞功能之间的复杂相互作用，并支持将 IMPs 转化为治疗由炎性单核细胞引起或增强的疾病的方法。
