Absence of PI3Kγ leads to increased leukocyte apoptosis and diminished severity of experimental autoimmune encephalomyelitis

Phosphatidylinositol-3-kinase gamma (PI3K gamma) plays an important role in the motility of leukocytes in several models of inflammation. In this work, the role of PI3K gamma in experimental autoimmune encephalomyelitis (EAE) was investigated. EAE was induced in wild-type and PI3K gamma deficient mice (PI3K gamma(-/-)). WT animals had a peak of clinical symptoms around day 14 post-induction (p.i.). PI3K gamma(-/-) animals developed milder EAE signs and peak of disease was noticed only on day 21 p.i. Better clinical outcome correlated with the absence of perivascular cuffs on day 14 p.i. and with decreased levels of CCL2 and CCL5 in brain of PI3K gamma(-/-) mice. There was increased leukocyte rolling and adhesion in pial vessels, as assessed by intravital microscopy, at day 14 after EAE induction in WT mice. The latter parameters were unaltered in PI3K gamma(-/-) mice subjected to EAE. Moreover, the PI3K gamma inhibitor AS-605240 given just before the intravital microscopy failed to affect leukocyte rolling or adhesion. Finally, there was a significant increase in the number of apoptotic cells in the CNS of EAE-induced PI3K gamma(-/-) mice. Our results suggest that PI3K gamma is involved in EAE and plays a more important role in mediating leukocyte survival than leukocyte adhesion in this experimental model of multiple sclerosis. (C) 2010 Elsevier B.V. All rights reserved.