Novel insights into immunological consequences of ischemic stroke

In recent years, dysregulation of the immune system has emerged as one of the most important pathophysiological cornerstones in stroke and its complications. Beyond prediction, improving patient outcomes and identifying novel targets for prevention are of great importance in stroke biomarker research. Important complicating events are stroke-associated infections, which are occurring in approximately one-third of cases, and are associated with worsened outcomes.¹ There is a complex relationship between infections and acute ischemic stroke, as infections cannot only follow but also precede stroke events.¹ While factors such as stroke severity and dysphagia significantly predict post-stroke infections, evidence from experimental and clinical settings indicates impaired immunity or brain-induced immunodepression following stroke.¹

Indeed, both local cerebral and systemic inflammatory responses occur following cerebral infarction, as recently summarised in a review by Simats et al. ² This process involves three key mechanisms. First, immediately after a stroke, acute immune system activation occurs in response to brain injury, triggering the release of immunoactive molecules known as damage-associated molecular patterns (DAMPs). These activate pattern recognition receptors (PRRs) on immune cells such as monocytes and macrophages, leading to increased pro-inflammatory cytokine release, including TNF-α and IL-6. Additionally, leucocyte activation is mediated by the autonomic nervous system, facilitating cell migration, e.g. from the gut and bone marrow. Second, a phase of immunosuppression follows, characterised by reduced circulating T, B, and NK cell counts, peripheral lymphopenia, and a shift from Th1 to Th2 helper T cells, accompanied by increased anti-inflammatory cytokines such as IL-10 and IL-4. The primary proposed mechanisms underlying this immunosuppression include prolonged sympathetic nervous system activation and hypothalamic-pituitary-adrenal axis activation; however, these remain controversial, with other mechanisms also proposed. Third, some patients may experience chronic low-grade inflammation. Potential markers of this persistent inflammation include elevated CRP and MCP-1 levels.² As opposed to persistent inflammation, measuring CRP, PCT, and IL-6, among other biomarkers, has been suggested as a strategy to identify patients at early risk of developing infections.³ While randomised controlled trials (RCTs) show no benefit from universal antibiotic use in large strokes⁴ , further RCTs will be needed to investigate whether risk stratification based on these biomarkers yields an additional benefit regarding the application of preventive anti-infective treatment.

Beyond post-stroke infections, patients who have suffered a stroke face a high risk of other complications including recurrent vascular events or cardiac dysfunction.⁵ Besides autonomic nervous system influences, reflected in e.g. ECG abnormalities, chronic inflammation, immune dysregulation, and vascular dysfunction again serve as common links between body and brain.^{2, 5} This interaction between inflammation and vasculopathy has been further demonstrated in a recent translational study by Cao et al.⁶ In mouse models, increased circulating cell-free DNA (cfDNA) post-stroke activated the AIM2 inflammasome, leading to increased matrix metalloproteinase (MMP) activity. Intriguingly, this mechanism was shown to degrade structural components of plaques, resulting in plaque destabilization and subsequent recurrent strokes. In experimental models, treatments neutralizing cfDNA with DNase or inhibiting inflammasome activation significantly reduced recurrent stroke rates. Analysis of carotid artery plaque samples from stroke patients confirmed increased inflammasome activation and MMP activity.⁶ Other work previously demonstrated the translational relevance of the central role of cfDNA in stroke pathophysiology.⁷ Higher cfDNA concentrations post-stroke were associated with unfavorable outcomes and higher 90-day mortality rates, also after adjusting for confounding factors.⁷ Furthermore, lower baseline DNase activity correlated with a higher risk of complications.

DNase activity and cfDNA may thus not only serve as future biomarkers for predicting patient prognosis and post-stroke complications but could even serve as novel therapeutic targets for preventing recurrent vascular events.⁷ The ongoing EXTEND-IA DNase⁸ and ResCIND⁹ trials are expected to provide valuable insights into this fascinating approach. Further current therapeutic approaches targeting inflammation are well summarised by Zietz et al., with three major ongoing strategies¹⁰: The first involves IL-6 inhibition, using drugs like Canakinumab, which has demonstrated benefits in reducing cardiovascular events in the CANTOS trial.¹¹ The second approach focuses on broad immunosuppression. While the CONVINCE trial, which investigated the efficacy of long-term colchicine therapy in preventing recurrent vascular events following non-cardioembolic stroke, did not show a clear benefit in reducing stroke recurrence or major cardiovascular complications¹², a meta-analysis involving patients with prior stroke or coronary disease showed beneficial results. It indicated a reduction in ischemic strokes without safety concerns, providing strong rationale to continue exploring this potentially relevant therapeutic approach despite the negative findings of the CONVINCE trial.¹³ The third strategy targets MCP-1/CCL2 blockade to stabilise atherosclerotic plaques, which is currently being studied in animal models.¹⁰

In summary, a range of immune system mechanisms is currently under investigation, offering promising prospects for the development of future therapeutic approaches to reduce the still high burden of stroke complications.

References:

1. Emsley, Hedley CA, and Stephen J. Hopkins. “Acute ischaemic stroke and infection: recent and emerging concepts.” The Lancet Neurology 7.4 (2008): 341-353.
2. Simats, Alba, and Arthur Liesz. “Systemic inflammation after stroke: implications for post‐stroke comorbidities.” EMBO molecular medicine 14.9 (2022): e16269.
3. Hasse, Isabel MC, et al. “Circulating inflammatory biomarkers in early prediction of stroke-associated infections.” International Journal of Molecular Sciences 23.22 (2022): 13747.
4. Westendorp, Willeke F., et al. “Preventive antibiotic therapy in acute stroke patients: A systematic review and meta-analysis of individual patient data of randomised controlled trials.” European stroke journal4 (2021): 385-394.
5. Simats, Alba, Hendrik B. Sager, and Arthur Liesz. “Heart–brain axis in health and disease: role of innate and adaptive immunity.” Cardiovascular Research (2024): cvae185.
6. Cao, Jiayu, et al. “DNA-sensing inflammasomes cause recurrent atherosclerotic stroke.” Nature 633.8029 (2024): 433-441.
7. Grosse, Gerrit M., et al. “Endogenous deoxyribonuclease activity and cell-free deoxyribonucleic acid in acute ischemic stroke: a cohort study.” Stroke 53.4 (2022): 1235-1244.
8. Bruce CV Campbell. Improving Early Reperfusion With Adjuvant Dornase Alfa in Large Vessel Ischemic Stroke (EXTEND-IA DNase). ClinicalTrials.gov identifier: NCT05203224. Updated June 28, 2024. Accessed March 9, 2025. https://clinicaltrials.gov/study/NCT05203224
9. Martin Dichgans. Reduction of SystemiC Inflammation After Ischemic Stroke by Intravenous DNase Administration (ReSCInD). ClinicalTrials.gov identifier: NCT05880524 Updated March 19, 2024. Accessed March 9, 2025. https://clinicaltrials.gov/study/NCT05880524?term=ResCIND&rank=1
10. Zietz, Annaelle, et al. “Targeting inflammation to reduce recurrent stroke.” International Journal of Stroke 19.4 (2024): 379-387.
11. Crossman, David, and Alexander Rothman. “The Canakinumab Antiinflammatory Thrombosis Outcome Study trial—the starting gun has fired.” Journal of Thoracic Disease 9.12 (2017): 4922.
12. Kelly, Peter, et al. “Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.” The Lancet 404.10448 (2024): 125-133.
13. Fiolet, Aernoud TL, et al. “Colchicine for secondary prevention of ischaemic stroke and atherosclerotic events: a meta-analysis of randomised trials.” EClinicalMedicine 76 (2024).