Thrombo-inflammation during ischaemia/reperfusion

Prof. Guido Stoll (University of Würzburg, Germany) reviewed T cell and platelet signalling pathways involved in thrombo-inflammation during ischaemia/reperfusion (I/R), and also discussed clinical trials targeting acute stroke-related inflammation [1].

Ischaemic stroke elicits a strong neuroinflammatory response in the acute and chronic stage, according to Prof. Stoll. However, the functional relevance and therapeutic potential of neuroinflammation have only recently become apparent. 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. Downstream activation of coagulation factor XII is a driving force of ischaemia–reperfusion injury in acute stroke.”

The evidence therefore suggests that during ischaemia–reperfusion injury, T cells interact with platelets and facilitate further infarct development through a complex process known as thrombo-inflammation.

However, in the majority of patients with ischaemic stroke, recanalization cannot be achieved. The contribution of neuroinflammation to permanent ischaemia and subacute stroke is less clear and more complex. Immune cells contribute to secondary infarct growth, but also to tissue remodelling. In certain settings, T cells aggravate neuronal damage late after the ischaemic insult, but stroke likewise induces a systemic immuno-depression syndrome which probably prevents stroke-induced autoimmunity to CNS antigens. Monocytes/macrophages, the main scavenger cells, in addition contribute to sealing of the damaged blood-brain barrier and thereby help to maintain haemostasis in the ischaemic brain.

Targeting stroke-related neuroinflammation may become an effective adjunct therapy to improve outcome after ischaemic stroke in the future, but requires caution with regard to timing and adverse effects. A number of studies have already investigated anti-inflammatory therapies, such as the MS drugs natalizumab and fingolimod, in acute stroke. In the placebo-controlled ACTION trial, natalizumab failed to reduce infarct volume growth, but was associated with improved clinical outcomes over 90 days [2]. Much more promising, according to Prof. Stoll, is fingolimod. The open-label FAMTAIS trial assesses effectiveness and safety of fingolimod combined with bridging therapy in large vessel occlusion acute ischemic stroke patients, and will control for recanalization [3,4].

1. Stoll G. EAN 2019, PLEN03_3.
2. Elkins J, et al. Lancet Neurol. 2017;16(3):217-26.
3. Zhu Z, et al. Circulation. 2015;132(12):1104-12.
4. Zhang S, et al. Int J Stroke. 2017;12(8):906-9.

 



Posted on 27 August 201918 March 2021