The Th17-ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease.
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.
Carlson
Thaddeus
T
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Kroenke
Mark
M
Rao
Praveen
P
Lane
Thomas E
TE
Segal
Benjamin
B
D019264:Adoptive Transfer; D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology*; D054360:Chemokine CXCL1 / Q000276:immunology*; D054426:Chemokine CXCL2 / Q000276:immunology*; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009186:Myelin Sheath / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000172:deficiency; D012008:Recurrence; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D023063:Receptors, Interleukin-8B