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Emmy Noether Junior Research Group - The role of brain-secreted alarmins as mediators of immunological comorbidities after stroke

  • Project Leader: Dr. Arthur Liesz
  • Affiliation: Institute for Stroke and Dementia Research (ISD)
  • Funding: since 2016

The peripheral immune response is a key element of the observed systemic effects after stroke. Subacute immunosuppression is a prominent phenomenon in the cascade of peripheral immune changes. However, studies of the applicant and others in recent years have shown that the acute phase after a stroke is characterized by a massive pro-inflammatory immune response and that there is a persistent systemic inflammation in the chronic phase. These observations have led to the current concept of a multiphasic immune response after stroke. In a recently published study, we were able to demonstrate that alarmines (pro-inflammatory mediators from necrotic cells) secreted after ischemia are key molecules in the initiation of this immunological cascade. Immunological mechanisms contribute significantly to the mortality and morbidity of stroke patients. The aim of this project is to investigate the role of alarmins as mediators of immune-mediated stroke comorbidities in the individual phases of the inflammatory cascade after ischemic brain damage. Here we will analyze the following special aspects: 1) the complex behavioral changes in the acute phase after stroke, which can be summarized as cytokine-induced sickness behavior, as a result of an alarmin-mediated cytokine storm. 2) Rapid change from immune activation to suppression in the subacute phase due to caspase-1-dependent pyropotic cell death of adaptive immune cells and cause of susceptibility to infection after stroke. 3) The accelerated atheroprogression in the chronic phase after stroke due to the persistent inflammatory response due to a chronic disorder of peripheral immune homeostasis. The aim of this project is to investigate the role of mediators in triggering the critical stroke comorbidities described above - disease behavior, immunosuppression and atherosclerosis - in the relevant temporal phases after stroke. We will investigate the mechanisms of disease development as well as potential therapeutic targets and therapeutic approaches. A better understanding of the pathomechanisms to be investigated has a direct translational relevance and will enable the development of possible therapeutics for immunological comorbidities in stroke patients. The three stroke comorbidities in the focus of this project contribute to a substantial part of the morbidity of stroke patients and may have a common trigger: the release of pro-inflammatory alarmins from the ischemic brain.

Source: GEPRIS (Text), University Hospital (Picture)