A conversation with Prof. Dr. Matthias Endres, MD, Director of the Department of Neurology, Charité-Universitätsmedizin, Berlin, Germany, on neuro-immune crosstalk in ischemic stroke.
Interviewed by Dr. Aurora Semerano, MD, Stroke Neurologist, San Raffaele Hospital, Milan, Italy (@semerano_aurora).
They will be discussing the article “Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke,” published in the April 15, 2022 issue of Circulation Research.
Dr. Semerano: Your article is part of a Compendium on Stroke and Neurocognitive Impairment published in Circulation Research, which includes several contributions about the advances made over the past five years in different fields of stroke research that were not addressed in the previous compendium. Which are, in your opinion, the most relevant advances in stroke immunology in these last five years?
Prof. Dr. Endres: First of all, thanks for including me in your blog, and thank you for very elaborate questions. Many of them would require a long answer, but I will try to be brief and refer interested readers to our review article instead.
Regarding the most important advances of the last five years — this is not an easy question. With regard to etiology and stroke risk, I think that recent large-scale genetic studies have led to a huge step forward to identify novel loci associated with stroke risk that can also be targeted pharmacologically. Personally, I find the work on clonal hematopoeisis and association with vascular and stroke risk very interesting. Regarding the acute phase of stroke, there are quite a number of high-quality publications on the complex role of the different players (i.e., neutrophils, monocytes, microglia, as well as T and B cells) in the ischemic cascade in the brain. Lastly, there is now a strong link between immune pathways following stroke and the development of post-stroke dementia (and also depression).
Dr. Semerano: What has the current COVID-19 pandemic taught us more about stroke immunology?
Prof. Dr. Endres: This is a VERY active field. One very important mechanism is immune thrombosis following SARS-CoV2 infection that leads also to an increased risk of stroke. There is a rather strong paragraph on COVID-19 in this article.
Dr. Semerano: Inflammation is increasingly recognized as a potential non-traditional risk factor for stroke. To date, what tools do we have to identify, measure, and prevent it?
Prof. Dr. Endres: Well, there are many blood biomarkers, such as CRP, Il-6, or MCP-1 (to name a few). Statins have also anti-inflammatory actions and are established in secondary prevention of stroke. Whether any of the compounds presently being tested in stroke prevention studies will make it into the clinic remains to be seen.
Dr. Semerano: Despite many efforts, until now, no immunotherapy has been demonstrated to achieve a relevant effect on clinical outcome in stroke. What are the main reasons for these failures?
Prof. Dr. Endres: This is hard to comment on in a few sentences. Regarding acute stroke treatment, there are no protective treatments (including immunotherapies) available other than thrombolysis and thrombectomy. For prevention, the situation is different — see, for example, the CANTOS trial. Certainly, it will be very interesting to see the results of the CONVINCE study that tests colchicine vs. placebo for secondary prevention of stroke patients.
Dr. Semerano: Does the heterogeneity of the immune response orchestrated after ischemic stroke represent a complication or a resource for the development of future immunotherapies?
Prof. Dr. Endres: Well, the pathophysiology is certainly very complex, but if we can decipher it correctly, it provides a huge opportunity for future therapies.
Dr. Semerano: Beyond its involvement in the acute phase of stroke, inflammation appears relevant for long-term stroke sequelae, such as post-stroke dementia and depression. Can you briefly explain to us how?
Prof. Dr. Endres: Please read the review for more details, but it seems at least that in rodent models later cognitive decline may be due to aberrant neurogenesis and chronic B lymphocyte activity.
Dr. Semerano: What are you working on at the moment?
Prof. Dr. Endres: Actually, on many projects (and not only on immune mechanisms). In animal models, we will continue to disentangle the role of blood-borne monocytes vs. microglia after stroke.
Dr. Semerano: What would you suggest for the designing of future clinical trials on immunomodulation?
Prof. Dr. Endres: I think treatment trials should be focused on selected patients based on valid biomarkers.
Dr. Semerano: Thanks very much for your time, Prof. Endres. It has been a pleasure chatting with you.