CD45 inhibits CD40L-induced microglial activation via negative regulation of the Src/p44/42 MAPK pathway

It has been reported that Ligation of CD40 with CD40 ligand (CD40L) results in microglial activation as evidenced by p44/42 mitogen-activated protein kinase (MAPK) dependent tumor necrosis factor alpha (TNF-alpha) production. Previous studies have shown that CD45, a functional transmembrane protein- tyrosine phosphatase, is constitutively expressed at moderate levels on mic roglial cells and this expression is greatly elevated on activated microgli a. To investigate the possibility that CD45 might modulate CD40L-induced mi croglial activation, we treated primary cultured microglial cells with CD40 L and anti-CD45 antibody. Data show that crosslinking of CD45 markedly inhi bits CD40L-induced activity of the Src family kinases Lck and Lyn. Further, cotreatment of microglia with CD40L and anti-CD45 antibody results in sign ificant inhibition of microglial TNF-alpha production through inhibition of p44/42 MAPK activity, a downstream signaling event resulting from Src acti vation. Accordingly, primary cultured microglial cells from mice deficient in CD45 demonstrate hyper-responsiveness to ligation of CD40, as evidenced by increased p44/42 MAPK activation and TNF-alpha production. Taken togethe r, these results show that CD45 plays a novel role in suppressing CD40L-ind uced microglial activation via negative regulation of the Src/p44/42 MAPK c ascade.