Platelet CD40L induces activation of astrocytes and microglia in hypertension

Studies have demonstrated separately that hypertension is associated with platelet activation in the periphery (resulting in accumulation and localized inflammatory response) and glial activation in the brain. We investigated the contribution of platelets in brain inflammation, particularly glial activation in vitro and in a rat model of hypertension. We found that HTN increased the expression of adhesion molecules like JAM-1, ICAM-1, and VCAM-1 on brain endothelium and resulted in the deposition of platelets in the brain. Platelet deposition in hypertensive rats was associated with augmented CD40 and CD40L and activation of astrocytes (GFAP expression) and microglia (Iba-1 expression) in the brain. Platelets isolated from hypertensive rats had significantly higher sCD40L levels and induced more prominent glial activation than platelets from normotensive rats. Activation of platelets with ADP induced sCD40L release and activation of astrocytes and microglia. Moreover, CD40L induced glial (astrocytes and microglia) activation, NFкB and MAPK inflammatory signaling, culminating in neuroinflammation and neuronal injury (increased apoptotic cells). Importantly, injection of ADP-activated platelets into normotensive rats strongly induced activation of astrocytes and microglia and increased plasma sCD40L levels compared with control platelets. On the contrary, inhibition of platelet activation by Clopidogrel or disruption of CD40 signaling prevented astrocyte and microglial activation and provided neuroprotection in both in vivo and in vitro conditions. Thus, we have identified platelet CD40L as a key inflammatory molecule for the induction of astrocyte and microglia activation, the major contributors to inflammation-mediated injury in the brain.