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Thrombo-inflammation in acute ischaemic stroke — implications for treatment

Nature Reviews Neurology volume 15, pages 473–481 (2019)Cite this article

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Abstract

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.

Key points

  • Ischaemic stroke elicits a strong neuroinflammatory response in the acute and chronic stage.

  • T cells contribute to ischaemia–reperfusion injury after recanalization in an antigen-independent manner.

  • During ischaemia–reperfusion injury, T cells interact with platelets and facilitate further infarct development through a complex process referred to as thrombo-inflammation.

  • In subacute and chronic stroke, detrimental T cell effects have to be balanced against lymphocyte-driven protective neuroinflammation.

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Fig. 1: Pathomechanisms of thrombus and embolus formation and thrombo-inflammation.

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Acknowledgements

Work in the authors’ laboratories was funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) – project number 374031971 – TRR 240 (CRC/TR 240 A1, A7 and B2). The authors thank I. Pleines for preparing the figure, M. Schuhmann for critical reading of the manuscript and numerous colleagues who contributed to the research cited in this article.

Peer review information

Nature Reviews Neurology thanks J. Anrather, A. Planas and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Neurology, University of Würzburg, Würzburg, Germany

    Guido Stoll

  2. University Hospital, University of Würzburg, Würzburg, Germany

    Guido Stoll & Bernhard Nieswandt

  3. Institute of Experimental Biomedicine, University of Würzburg, Würzburg, Germany

    Bernhard Nieswandt

  4. Rudolf Virchow Centre, University of Würzburg, Würzburg, Germany

    Bernhard Nieswandt

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G.S. provided a first draft of the Review, which was jointly completed by G.S. and B.N.

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Correspondence to Guido Stoll.

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Glossary

Apparent diffusion coefficient

A measure that reflects the diffusion speed of water molecules. This measure is determined by brain MRI to identify areas of impending or manifest ischaemic cell death and the extent of these areas in patients with acute stroke; in these areas, the apparent diffusion coefficient is reduced.

Kallikrein–kinin system

A plasma and tissue proteolytic system that leads to liberation of the vasoactive pro-inflammatory mediator bradykinin. Coagulation factor XIIa cleaves prekallikrein into its proteolytically active form kallikrein, which in turn activates high-molecular-mass kininogen to generate bradykinin. Activated factor XII thereby links thrombotic and inflammatory pathways.

Haemostasis

A complex process that involves activation and interaction of platelets with soluble coagulation factors to rapidly stop bleeding.

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Stoll, G., Nieswandt, B. Thrombo-inflammation in acute ischaemic stroke — implications for treatment. Nat Rev Neurol 15, 473–481 (2019). https://doi.org/10.1038/s41582-019-0221-1

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