Overlapping roles of P-selectin and α4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis

SM Kerfoot, P Kubes - The Journal of Immunology, 2002 - journals.aai.org
The Journal of Immunology, 2002journals.aai.org
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 …
Abstract
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 α 4 integrin increased with time as anti-α 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 α 4 integrin Ab-treated mice blocked all remaining rolling at each time point. Interestingly, however, α 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 α 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 α 4 integrin in mediating leukocyte-endothelial cell interactions.
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