Acute ischemic stroke is one of the leading causes of death throughout the world. Acute stroke treatment focuses on thrombolysis, but despite successful recanalization ischemic lesions may further grow. The pathophysiology of this so-called reperfusion injury is not well understood. Essential pathogenic factors such as thrombocytes, T-cells, the contact activation system and the neuronal calcium homeostasis have been identified but their mechanistic connection and key interactions remain unclear. We postulate thrombo-inflammatory cell-cell interactions at the neurovascular unit as the major pathomechanism of infarct propagation in the acute ischemic brain. To visualize, quantify and map such cell-cell interactions, we will use high-resolution transcranial Twophoton and Light-sheet Microscopy in the ischemic brain. Knock-out of individual essential pathogenic factors will finally allow for molecular analysis and a model of the main interacting partners in the ischemic brain. We expect fundamental insights into cell-cell interactions underlying reperfusion injury in the brain.