Banisadr Ghazal, Schwartz Samantha R, Podojil Joseph R, Piccinini Linda A, Lanker Stefan, Miller Stephen D, Miller Richard J
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E Superior St, Chicago, IL, 60611, USA,
J Neuroimmune Pharmacol. 2014 Jun;9(3):438-45. doi: 10.1007/s11481-014-9521-9. Epub 2014 Jan 30.
Excessive infiltration of leukocytes and the elaboration of inflammatory cytokines are believed to be responsible for the observed damage to neurons and oligodendrocytes during multiple sclerosis (MS). Blocking adhesion molecules or preventing the effects of chemotactic mediators such as chemokines can be exploited to prevent immune cell recruitment to inflamed tissues. An anti-α4 integrin antibody (anti-VLA-4mAb/natalizumab (Tysabri®)) has been used as a treatment for MS and reduces leukocyte influx into the brain. In patients, anti-VLA-4 reduces relapses and disability progression. However, its mechanism of action in the brain is not completely understood. The anti-VLA-4mAb was demonstrated to mobilize hematopoietic progenitor cells. Interestingly, the chemokine SDF-1/CXCL12 and its receptor CXCR4 are also key factors regulating the migration of hematopoietic stem cells. Moreover, studies have revealed a crosstalk between SDF-1/CXCR4 and VLA-4 signaling in regulating cell migration. In this study, we address the effects of anti-VLA-4 on chemokine signaling in the brain during MS. We assessed the ability of anti-VLA-4 to regulate Experimental Autoimmune Encephalomyelitis (EAE) and chemokine/receptor signaling. Preclinical administration of anti-VLA-4 delayed clinical signs of EAE. We found that anti-VLA-4 treatment reduced chemokine expression. In order to further explore the interaction of anti-VLA-4 with chemokine/receptor signaling we used dual color transgenic mice. After EAE induction, the expression of both SDF-1/CXCL12 and CXCR4 receptor was upregulated, treatment with anti-VLA-4 inhibited this effect. The effects of anti-VLA-4 on chemokine signaling in the CNS may be of importance when considering its mechanism of action and understanding the pathogenesis of EAE.
白细胞的过度浸润以及炎症细胞因子的产生被认为是导致多发性硬化症（MS）期间观察到的神经元和少突胶质细胞损伤的原因。阻断黏附分子或阻止趋化介质（如趋化因子）的作用可用于防止免疫细胞募集到炎症组织。抗α4整合素抗体（抗VLA-4单克隆抗体/那他珠单抗（Tysabri®））已被用作MS的治疗药物，并可减少白细胞流入大脑。在患者中，抗VLA-4可减少复发和残疾进展。然而，其在大脑中的作用机制尚未完全了解。抗VLA-4单克隆抗体被证明可动员造血祖细胞。有趣的是，趋化因子SDF-1/CXCL12及其受体CXCR4也是调节造血干细胞迁移的关键因素。此外，研究揭示了SDF-1/CXCR4与VLA-4信号在调节细胞迁移方面存在相互作用。在本研究中，我们探讨了抗VLA-4对MS期间大脑中趋化因子信号的影响。我们评估了抗VLA-4调节实验性自身免疫性脑脊髓炎（EAE）和趋化因子/受体信号的能力。抗VLA-4的临床前给药延迟了EAE的临床症状。我们发现抗VLA-4治疗降低了趋化因子的表达。为了进一步探索抗VLA-4与趋化因子/受体信号的相互作用，我们使用了双色转基因小鼠。在诱导EAE后，SDF-1/CXCL12和CXCR4受体的表达均上调，抗VLA-4治疗可抑制这种作用。考虑到抗VLA-4的作用机制以及理解EAE的发病机制时，其对中枢神经系统中趋化因子信号的影响可能具有重要意义。
