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PMID: 18347102 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of experimental medicine ·Vol. 205 ·No. 4 ·2008-04-14 ·Pages 811-23

Carlson T, Kroenke M, Rao P, Lane TE, Segal B

Abstract

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.

MeSH Terms
Adoptive Transfer Animals Autoimmune Diseases of the Nervous System/immunology,pathology,prevention & control Blood-Brain Barrier/immunology,pathology Bone Marrow Cells/immunology Central Nervous System/immunology,pathology Chemokine CXCL1/immunology Chemokine CXCL2/immunology Inflammation Leukocytes, Mononuclear/immunology Mice Mice, Inbred BALB C Myelin Sheath/immunology Receptors, Interleukin-8B/deficiency Recurrence T-Lymphocytes, Helper-Inducer/immunology
Chemicals
Chemokine CXCL1 Chemokine CXCL2 Receptors, Interleukin-8B
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Carlson Thaddeus
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Kroenke Mark
Rao Praveen
Lane Thomas E
Segal Benjamin
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20072404
Published
2008-04-14
Epub
2008-00-17
Pages
811-23
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2292221
Subset
IM
Grants
NINDS NIH HHS · R01 NS041249 · United States
NINDS NIH HHS · R01 NS047687 · United States
NINDS NIH HHS · NS047687-01A1 · United States
NINDS NIH HHS · NS041249 · United States
External Links
PubMed source DOI: 10.1084/jem.20072404 PMC Full Text View journal details
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