By: Nicolas Martinez-Majander, Adam Denes, and Robin Lemmens
ESO Garmisch Stroke Science Workshop 2021
Session 4: Stroke and Inflammation
During the last session on Friday at the ESO Garmisch Stroke Science Workshop the association between inflammation and stroke was discussed, with a clear focus on preclinical research. This session was convened by Dr Adam Denes (Hungary) and Dr Robin Lemmens (Belgium).
The session started with a keynote lecture by Dr Catherine Lawrence “Anti-inflammatory therapies for acute stroke – The impact of co-morbidity”.
After presenting the basic mechanisms of inflammation in acute stroke, Dr Lawrence summarized the clinical trials to date that have targeted inflammatory markers and pathways, amongst others with anti-CD11+CD18 and anti-ICAM-1. However, these trials were mainly neutral or, in some cases, even harmful. Ongoing clinical trials are exploring drugs such as fingolimod and dimethyl fumarate. She clearly stressed the importance of a better understanding of inflammation mechanisms in CNS after stroke, including local proliferation of immune cell in addition to CNS invasion.
Furthermore, Dr Lawrence pointed out that most of the stroke patients have co-morbidities such as diabetes, hypertension, and obesity (increasing the levels of CCLL2 and ICAM) that may alter the inflammatory state. These modifiers have insufficiently been incorporated in preclinical research. In animal models of obesity, low-grade systemic inflammation already present prior to stroke is associated with increased ischemic damage and might also impair the response to anti-inflammatory treatments.
After the keynote lecture, Dr Denis Vivien (France) highlighted the potential of functional ultrasound and vascular magnetic resonance imaging in experimental stroke. E.g. VCAM-1 constitutes a relevant target for molecular imaging of atherosclerotic lesions. Studies have also explored other types of adhesion molecules, such as P-selectin in TIA revealing inflammatory processes in different organs. Detecting P-selectin sensitive cells might also predict good response to anti-inflammatory treatments. Furthermore, Dr Vivien gave an overview on how fast ultrasound imaging could improve early diagnosis of ischemic stroke and how it could be utilized in monitoring response to tPA.
Next, Dr Arthur Liesz (Germany) addressed the role of the inflammasomes and implications for stroke therapeutics. There is a systemic inflammasome activation after stroke, especially of the AIM2 inflammasomes that are systemically activated by cell-free DNA in stroke patients. This further affects the levels of IL-1b, increasing the risk of a recurrent stroke due to accelerated atherosclerosis. In an animal model for carotid atherosclerosis distant stroke induced inflammation in the carotid plaque and was associated with secondary cerebral infarcts. Targeting inflammasomes to block cellular inflammation in the plaque with e.g. caspase-1 inhibition might decrease the risk of recurrent atherosclerotic stroke. Furthermore, the inflammasome activation might lead to secondary infections such as pneumonia.
After these presentations regarding the cellular and molecular mechanisms through which inflammation may contribute to the pathophysiology of stroke, the session was closed by Dr Marios Georgakis (Germany) who discussed the developments of preventative anti-inflammatory approaches for atherosclerotic stroke. He presented results from several clinical trials such as CANTOS, COLCOT, LoDoCo2. These trials explored the effect of canakinumab and colchicine on preventing recurrent events but none of them included patients with a recent stroke. Dr Georgakis also discussed how several studies have shown an association between IL-6 and the risk of ischemic stroke, especially strokes caused by large artery atherosclerosis. However, the benefits of targeting IL-6 are shown to be outweighed by its side effects. Other targets with less side effects include e.g. CCL2/CCR2 pathway in atherosclerosis. The efficacy and safety of colchicine in reducing recurrent events in stroke patients is currently being explored by two ongoing trials, CONVINCE and CASPER.
Many thanks to the convenors and invited speakers for this intriguing session and we are looking forward to the presentations and lively discussion on Saturday as well!