Regulation of Leukocyte Integrins in Inflammatory Cell Recruitment

白细胞整合素在炎症细胞募集中的调节

• 批准号: 8175342
• 负责人: Triantafyllos Chavakis
• 金额: $ 31.76万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8175342
• 关键词: Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autoimmune Process; Blood Platelets; Brain; CD18 Antigens; Cell Adhesion; Cells; Clinical; Endothelial Cells; Endothelium; Experimental Autoimmune Encephalomyelitis; Eye; Human; Inflammatory; Inflammatory Response; Integrins; Leukocytes; Lung; Mediating; Molecular; Multiple Sclerosis; Mus; Organ; Play; Process; Regulation; Role; Spinal Cord; brain tissue; chromosome 1 loss; inhibitor/antagonist; monocyte

Leukocyte integrins and beta2-integrins in particular, play a crucial role in mediating leukocyte-endothelial interactions and thereby leukocyte recruitment. Leukocyte integrins are thereby important targets to therapeutically interfere with leukocyte recruitment in inflammatory and autoimmune diseases. (a) We have recently identified that developmentally regulated endothelial locus-1 (Del-1) is an endogenous inhibitor of leukocyte recruitment. Del-1 is produced and secreted by endothelial cells. Del-1 expression is found in the lung and in the immunoprivileged tissues brain and eye. We identified that endothelial-derived Del-1 acts to inhibit beta2-integrin-dependent leukocyte adhesion to the endothelium and thereby leukocyte recruitment. Thus, Del-1 is an endogenous anti-inflammatory factor. Del-1-deficient mice displayed higher levels of inflammatory cell recruitment. Since Del-1 expression is high in the brain and eye, the role of Del-1 is currently evaluated in inflammatory and autoimmune processes of these organs. (b) Blood platelets may be involved in the process of leukocyte recruitment. In particular, blood platelets may adhere to the activated endothelium and form a bridge that promotes the arrest of inflammatory cells such as monocytes. I.e. platelets can contribute significantly to inflammatory cell recruitment. We are currently investigating the role of platelets in mediating inflammatory cell recruitment in the context of inflammatory and autoimmune diseases. We have found that platelet depletion reduced inflammatory cell recruitment to the spinal cord and the overall inflammatory response in the course of experimental autoimmune encephalomyelitis, which is the mouse counterpart of human multiple sclerosis. Moreover, platelet depletion resulted in suppression of the clinical score of experimental autoimmune encephalomyelitis in mice.

尤其是白细胞结构和β2-积聚蛋白，在介导白细胞 - 内皮相互作用并从而募集白细胞中起着至关重要的作用。因此，白细胞整合蛋白是治疗性干扰炎症和自身免疫性疾病中白细胞募集的重要靶标。 （a）我们最近确定，受发展调控的内皮基因座-1（del-1）是白细胞募集的内源性抑制剂。 DEL-1由内皮细胞产生和分泌。 DEL-1表达在肺部和免疫动物组织脑和眼睛中发现。我们确定内皮衍生的DEL-1作用是抑制β2-整合素依赖性白细胞对内皮的粘附，从而抑制白细胞募集。因此，DEL-1是内源性抗炎因子。 DEL-1缺陷小鼠显示出更高水平的炎性细胞募集。 由于DEL-1表达在大脑和眼睛中较高，因此DEL-1的作用目前在这些器官的炎症和自身免疫过程中进行评估。 （b）血小板可能参与白细胞募集的过程。特别是，血小板可能粘附在活化的内皮上，并形成桥梁，促进炎性细胞（如单核细胞）的停滞。 IE。血小板可以对炎症细胞募集产生重大贡献。我们目前正在研究血小板在炎症和自身免疫性疾病的背景下介导炎症细胞募集的作用。我们发现，在实验性自身免疫性脑脊髓炎的过程中，血小板耗竭可降低脊髓的炎症细胞募集以及总体炎症反应，这是人类多发性硬化症的小鼠对应物。此外，血小板耗竭导致抑制小鼠实验自身免疫性脑脊髓炎的临床评分。

项目成果

Regulation of integrin activity and signalling.

• DOI: 10.1016/j.bbagen.2009.03.007
• 发表时间: 2009-06
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
• 影响因子: 3
• 作者: Gahmberg, Carl G.;Fagerholm, Susanna C.;Nurmi, Susanna M.;Chavakis, Triantafyllos;Marchesan, Silvia;Gronholm, Mikaela
• 通讯作者: Gronholm, Mikaela