Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Germany; Clinic of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt am Main, Frankfurt, Germany.
Eur J Immunol. 2014 Sep;44(9):2648-58. doi: 10.1002/eji.201343968. Epub 2014 Jun 30.
Acute inflammation is the pathophysiological basis of important clinical conditions associated with organ failure. The initial inflammatory response is controlled by the chemokine system, yet recent data have indicated that the neuronal guidance cues are significantly involved in the orchestration of this process. Previous work has shown the proinflammatory capacity of the guidance cue semaphorin (Sema) 7a, but the role of one of its target receptors, the plexin C1 (PLXNC1) receptor is to date unknown. We report here that PLXNC1 is expressed outside the nervous system and induced during acute inflammation. PLXNC1(-/-) mice with C57BL/6 background demonstrated decreased inflammatory responses during zymosan A (ZyA)-induced peritonitis. Subsequent in vivo studies revealed altered rolling, adhesion, and transmigration properties of PLXNC1(-/-) leukocytes. Blockade of PLXNC1 was associated with attenuated chemotactic transendothelial migration properties in vitro. Studies in chimeric mice revealed that hematopoietic PLXNC1(-/-) animals demonstrated an attenuated inflammatory response. To probe the therapeutic potential of PLXNC1 we treated C57BL/6 WT mice with an anti-PLXNC1 antibody and a PLXNC1 binding peptide. Both of these interventions significantly dampened ZyA-induced peritonitis. These results implicate an important role of PLXNC1 during an acute inflammatory response and indicate PLXNC1 as a potential target for the control of conditions associated with acute inflammation.
急性炎症是与器官衰竭相关的重要临床病症的病理生理基础。初始炎症反应受趋化因子系统控制，但最近的数据表明神经元导向线索在这一过程的协调中起着重要作用。先前的工作表明，导向线索神经纤毛蛋白 7a（Sema7a）具有促炎能力，但到目前为止，其靶受体之一的丛蛋白 C1（PLXNC1）受体的作用尚不清楚。我们在此报告，PLXNC1 在神经系统外表达，并在急性炎症时被诱导。具有 C57BL/6 背景的 PLXNC1（-/-）小鼠在酵母聚糖 A（ZyA）诱导的腹膜炎中表现出炎症反应降低。随后的体内研究显示 PLXNC1（-/-）白细胞的滚动、黏附和迁移特性发生改变。PLXNC1 阻断与体外趋化性跨内皮迁移特性减弱相关。嵌合小鼠研究表明，造血 PLXNC1（-/-）动物表现出炎症反应减弱。为了探究 PLXNC1 的治疗潜力，我们用抗-PLXNC1 抗体和 PLXNC1 结合肽治疗 C57BL/6 WT 小鼠。这两种干预都显著减轻了 ZyA 诱导的腹膜炎。这些结果表明 PLXNC1 在急性炎症反应中起着重要作用，并表明 PLXNC1 可能是控制与急性炎症相关疾病的潜在靶点。
