Thrombo-inflammation in acute ischaemic stroke — implications for treatment

Ischaemic stroke elicits a strong neuroinflammatory response, but the functional relevance and therapeutic potential of neuroinflammation has only recently become apparent. In acute experimental stroke, T cells contribute to ischaemia–reperfusion injury after recanalization in an antigen-independent manner. Surprisingly, the detrimental T cell effects are platelet-dependent. Glycoprotein (GP)Ib-mediated and GPVI-mediated platelet activation, but not GPIIb–IIIa-mediated platelet aggregation, is an important checkpoint that orchestrates thrombotic and pro-inflammatory pathways, and downstream activation of coagulation factor XII is a driving force of ischaemia–reperfusion injury in acute stroke. The evidence therefore suggests that T cells interact with platelets and facilitate further infarct development through a complex process that we refer to as thrombo-inflammation. Results of clinical trials of agents that target lymphocytes support this concept. However, in the majority of patients with ischaemic stroke, recanalization cannot be achieved and the contribution of T cells in the setting of the resultant permanent ischaemia and subacute stroke is less clear and more complex. In some settings, T cells still seem to aggravate neuronal damage late after the ischaemic insult, but stroke triggers systemic immunodepression, therefore further anti-inflammatory treatments would need to be used carefully in this context. Targeting stroke-related neuroinflammation could become an effective adjunct therapy to improve outcomes after ischaemic stroke, but this approach will require caution regarding the timing and avoidance of adverse effects. Ischaemic stroke causes a neuroinflammatory response, but the functional consequences of this response have been unclear. In this Review, Stoll and Nieswandt consider the roles of T cells, platelets and their interactions in this neuroinflammatory response and how these roles could be exploited therapeutically.