The Journal of Experimental Medicine
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Published online March 17, 2008
doi:10.1084/jem.20072404
The Journal of Experimental Medicine, Vol. 205, No. 4, 811-823
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Carlson et al.
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ARTICLE

 The Th17–ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease

Thaddeus Carlson1, Mark Kroenke1, Praveen Rao1, Thomas E. Lane3, and Benjamin Segal1,2

1 Department of Microbiology and Immunology and 2 Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
3 Department of Molecular Biology and Biochemistry and Center for Immunology, University of California, Irvine, Irvine, CA 92697

CORRESPONDENCE Benjamin M Segal: bmsegal{at}umich.edu

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.

Abbreviations used: BBB, blood–brain barrier; BMMac, enriched bone marrow macrophages; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; NP, influenza nucleoprotein; NRS, normal rabbit serum; PGRP, peptidoglycan recognition protein; PLP, proteolipid protein.


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