Brain-released alarmins as mediators of immunological comorbidities after stroke

• Applicant: Professor Dr. Arthur Liesz
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289539980

Alteration of the peripheral immune system is a key feature of systemic effects after acute stroke. One prominent phenomenon of post-stroke immunomodulation is an immunosuppressive syndrome in the subacute phase after stroke. However, recent works by the applicant and others have demonstrated a strong over-activation of peripheral immunity in the acute phase and a low-grade chronic inflammatory state in the chronic phase after experimental and clinical stroke. These findings have generated the novel concept of a multiphasic systemic immune reaction to acute stroke. We have shown in a recent proof-of-principle study that brain-released alarmins - pro-inflammatory molecules released from necrotic brain tissue - are key mediators initiating this multiphasic dysbalance of peripheral immune homeostasis after stroke. Immunological mechanisms contribute substantially to morbidity and mortality of stroke patients. The general aim of this project is to investigate the role of alarmins as an upstream mediator of multiple critical comorbidities observed in stroke patients at distinct phases within the immunological cascade after stroke. Therefore, we hypothesize that brain-released alarmins might play a crucial role in mediating: 1) the complex behavioral changes in the acute phase - known as cytokine-induced sickness-behavior - due to an alarmin-driven acute cytokine-storm. 2) the immunophenotypical switch from immune activation to suppression in the subacute phase due to caspase 1-dependent pyroptotic cell death of adaptive immune cells and cause of increased susceptibility to bacterial infections after stroke. 3) the exacerbation of atherosclerosis in the chronic stages after stroke due to alarmin-mediated, dysbalanced immune homeostasis and chronic inflammation. The purpose of this project is to investigate the potential role of alarmins in mediating these critical comorbidities of stroke - sickness behavior, immunosuppression and chronic vascular inflammation - in their distinct phases after stroke. We will analyze the underlying mechanisms and potential drug targets in these novel disease pathways. Better understanding of alarmin-driven immunological cascades after stroke are of direct translational relevance with potential clinical use. The three investigated stroke comorbidities contribute to a large proportion of post-stroke complications and morbidity and might have one common trigger: the release of pro-inflammatory alarmins after stroke.

• DFG Programme: Independent Junior Research Groups