Carlson Thaddeus, Kroenke Mark, Rao Praveen, Lane Thomas E, Segal Benjamin
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
J Exp Med. 2008 Apr 14;205(4):811-23. doi: 10.1084/jem.20072404. Epub 2008 Mar 17.
The ELR(+) CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4(+) Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood-brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2(+) PMN into CXCR2(-/-) mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17-ELR(+) CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide-sensitized mice, and suggest new therapeutic targets for diseases such as MS.
在多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）中，ELR（+）CXC趋化因子CXCL1和CXCL2在中枢神经系统（CNS）中上调。然而，它们的功能意义以及调节其表达的途径在很大程度上尚不清楚。我们发现，致脑炎性CD4（+）Th17细胞的转移足以在同基因的未接触过抗原的受体脊髓中诱导CXCL1和CXCL2转录。CXCR2是这些趋化因子在小鼠中的主要受体，对其进行阻断或基因沉默可消除血脑屏障（BBB）的破坏、白细胞浸润中枢神经系统以及在EAE发病期和复发期临床缺陷的发展。循环多形核白细胞（PMN）的耗竭具有类似的治疗效果。此外，向CXCR2（-/-）小鼠注射CXCR2（+）PMN足以恢复其对EAE的易感性。我们的研究结果表明，Th17-ELR（+）CXC趋化因子途径对于髓磷脂肽致敏小鼠的粒细胞动员、血脑屏障破坏以及自身免疫性脱髓鞘的临床表现至关重要，并为MS等疾病提出了新的治疗靶点。
