Abstract
Introduction: Acute ischemic stroke (AIS) is a potent trigger of immunosuppression, resulting in increased infection risk. While thrombolytic therapy with tissue-type plasminogen activator (t-PA) is still the only pharmacological treatment for AIS, plasmin, the effector protease, has been reported to suppress dendritic cells (DCs), known for their potent antigen-presenting capacity. Accordingly, in the major group of thrombolyzed AIS patients who fail to reanalyze (>60%), t-PA might trigger unintended and potentially harmful immunosuppressive consequences instead of beneficial reperfusion. To test this hypothesis, we performed an exploratory study to investigate the immunomodulatory properties of t-PA treatment in a mouse model of ischemic stroke.Methods: C57Bl/6J wild-type mice and plasminogen-deficient (plg−/−) mice were subjected to middle cerebral artery occlusion (MCAo) for 60 min followed by mouse t-PA treatment (0.9 mg/kg) at reperfusion. Behavioral testing was performed 23 h after occlusion, pursued by determination of blood counts and plasma cytokines at 24 h. Spleens and cervical lymph nodes (cLN) were also harvested and characterized by flow cytometry.Results: MCAo resulted in profound attenuation of immune activation, as anticipated. t-PA treatment not only worsened neurological deficit, but further reduced lymphocyte and monocyte counts in blood, enhanced plasma levels of both IL-10 and TNFα and decreased various conventional DC subsets in the spleen and cLN, consistent with enhanced immunosuppression and systemic inflammation after stroke. Many of these effects were abolished in plg−/− mice, suggesting plasmin as a key mediator of t-PA-induced immunosuppression.Conclusion: t-PA, via plasmin generation, may weaken the immune response post-stroke, potentially enhancing infection risk and impairing neurological recovery. Due to the large number of comparisons performed in this study, additional pre-clinical work is required to confirm these significant possibilities. Future studies will also need to ascertain the functional implications of t-PA-mediated immunosuppression for thrombolyzed AIS patients, particularly for those with failed recanalization.
Highlights
Acute ischemic stroke (AIS) is a potent trigger of immunosuppression, resulting in increased infection risk
Since type plasminogen activator (t-PA) and plasmin are broadly involved in processes independent of fibrinolysis [4, 18], there is a need to unravel possible nonhaemostatic effects of t-PA when it is used at the pharmacological, “exaggerated” concentrations
Middle Cerebral Artery Occlusion (MCAo) for 1 h induced a profound motor function deficit 23 h after occlusion, but this outcome was significantly worsened in C57Bl/6J mice receiving t-PA, demonstrating the potential of t-PA to mediate harmful effects during its use in stroke
Summary
Acute ischemic stroke (AIS) is a potent trigger of immunosuppression, resulting in increased infection risk. In the major group of thrombolyzed AIS patients who fail to reanalyze (>60%), t-PA might trigger unintended and potentially harmful immunosuppressive consequences instead of beneficial reperfusion To test this hypothesis, we performed an exploratory study to investigate the immunomodulatory properties of t-PA treatment in a mouse model of ischemic stroke. Plasmin has been well-characterized as a pro-inflammatory mediator [8], and more recently associated with immunosuppressive effects via the shutdown of dendritic cells (DC), thereby inducing a tolerogenic phenotype [9] Such immunomodulatory consequences of thrombolytic therapy would be undesirable for stroke patients, who are susceptible to infections (such as pneumonia) due to the development of a central nervous system (CNS) injury-induced immunosuppression [10] and increased gut permeability, allowing the migration of bacteria from the gastrointestinal tract into the circulation [11]
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