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4 Integrin to Recruit Leukocytes to the Central Nervous System in Experimental Autoimmune Encephalomyelitis1
Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
Experimental autoimmune encephalomyelitis (EAE) is mediated by
inflammatory cells recruited from the circulation to the CNS. We used
intravital microscopy to investigate the mechanisms of this
recruitment. No leukocyte rolling and very little adhesion was observed
in healthy control mice. In contrast, both rolling and adhesion was
observed in brain postcapillary venules before onset of physical
symptoms of EAE. Rolling and adhesion remained elevated for 2 wk and
returned to near normal levels by 5 wk postsymptom onset. Consistent
with a role for P-selectin in recruitment to the CNS, P-selectin
protein was detected in the brains and spinal cords of EAE mice.
Expression was highest before symptom onset and decreased over the next
2 wk. The importance of 
4 integrin increased with time
as anti-4 integrin blocked 
20, 50, and 60% of
leukocyte rolling 2 days before disease onset, 5 days and 2 wk
postonset of symptoms, respectively, and 85% of rolling 5 wk
postsymptoms. Addition of anti-P-selectin to 4
integrin Ab-treated mice blocked all remaining rolling at each time
point. Interestingly, however, 4 integrin-mediated
rolling appeared to be entirely dependent on P-selectin as
anti-P-selectin alone was able to completely block all leukocyte
rolling. In the absence of rolling (with P-selectin Ab), a 70%
reduction in adhesion was noted. A very similar reduction was seen when
mice were treated with 4 integrin-blocking Ab. In
conclusion, we describe increased leukocyte trafficking in the brains
of EAE mice with important overlapping roles for both P-selectin and
4 integrin in mediating leukocyte-endothelial cell
interactions.
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