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 inthe central nervous system (CNS) during multiple sclerosis (MS)and its animal model, experimental autoimmune encephalomyelitis(EAE). However, their functional significance and the pathwaysregulating their expression are largely unknown.

We show thattransfer of encephalitogenic CD4⁺ Th17 cells is sufficient toinduce CXCL1 and CXCL2 transcription in the spinal cords ofnaive, syngeneic recipients. Blockade or genetic silencing ofCXCR2, a major receptor for these chemokines in mice, abrogatesblood–brain barrier (BBB) breakdown, CNS infiltrationby leukocytes, and the development of clinical deficits duringthe presentation as well as relapses of EAE. Depletion of circulatingpolymorphonuclear leukocytes (PMN) had a similar therapeuticeffect. Furthermore, injection of CXCR2⁺ PMN into CXCR2^–/– mice was sufficient to restore susceptibility to EAE. Our findingsreveal that a Th17–ELR⁺ CXC chemokine pathway is criticalfor granulocyte mobilization, BBB compromise, and the clinicalmanifestation of autoimmune demyelination in myelin peptide–sensitizedmice, and suggest new therapeutic targets for diseases suchas MS.

Abbreviations used:

1. BBB, blood–brain barrier;
2. BMMac, enrichedbone marrow macrophages;
3. CNS, central nervous system;
4. EAE, experimentalautoimmune encephalomyelitis;
5. MS, multiple sclerosis;
6. NP, influenzanucleoprotein;
7. NRS, normal rabbit serum;
8. PGRP, peptidoglycan

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