ImmunoStroke: From Immune cells to stroke recovery.Plasma-kallikrein mediated modulation of T cells and microglia responses during long-term stroke recovery.

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Plasma kallikrein (PK), a key component of the kallikrein-kinin system (KKS), represents one of the most promising novel therapeutic targets for stroke therapy due to its proinflammatory and prothrombotic dual role. Indeed, we have demonstrated that acute ischemic stroke triggers PK activation, while both pharmacological inhibition and genetic deletion of PK significantly reduce intracerebral thrombus formation and blood-brain barrier damage. Strikingly, our preliminary data indicate that direct blocking of PK also improves functional long-term recovery together with a reduction in brain-infiltrating T cells upon stroke. However, it still remains elusive how PK, a soluble molecule acting in the blood plasma, interferes with the immune environment. Thus, we will deeply immunophenotype the functional state of T cells and microglia after PK inhibition using cutting-edge transcriptomics, immunomics, and proteomics analysis. However, from the clinical perspective, the concept of PK inhibition in stroke is still at the earliest stage of clinical translation since human-tailored PK inhibitors are currently not available. Therefore, novel targets mechanistically related to PK could lead to already validated therapeutic options or even marketed, i.e., drug repurposing. Specifically, recent breakthroughs in genetics and bioinformatics united in systems medicine have revolutionized the concept of medicine also providing new strategies to identify novel therapeutic targets. Therefore, through implementing a novel systems medicine approach, we aim to identify de novo therapeutic targets mechanistically related to PK and the KKS, which could maximally reduce the time required for successful clinical implementation. Finally, we aim to elucidate the molecular interactions between PK-T cells and PK-microglia under ischemic conditions, which are still not completely understood. In fact, PK directly activates the protease-activated receptors (PARs), broadly expressed by various cell types including T cells and microglia. Importantly, our preliminary data indicate an upregulated expression of PARs in brain-infiltrating T cells from stroked mice. Precisely, T cells from ischemic brains directly upregulate PAR1-4 expression, whereas anti-PK treatment seems to downregulate PAR expression specifically in T cells. Thus, we intend to analyse the functional interaction between PAR, T cells, and microglia upon treatment with serum from anti-PK treated stroked mice or purified PK to further correlate these results with our transcriptomics and proteomics data. Hence, we here aim to ultimately elucidate the most relevant underlying mechanisms of PK-T cell and PK-microglia interaction involved in long-term stroke recovery while identifying new potential mechanistic-related PK targets to promote rapid clinical translation.