Regulatory mechanisms of temporal microglia phenotype expression in a neonatal rat model of infection-sensitized hypoxic ischemic brain injury
Final Report Abstract
Approximately one million term newborns die each year as a result of acute oxygen deprivation during birth. This birth complication is very common in developing countries, and is one of the main causes of death in newborns worldwide. The standard therapy in industrialized countries to treat the consequences of acute oxygen deficiency is therapeutic hypothermia. About 30- 50% of affected newborns do not benefit from the therapy. Unfortunately, the therapy has so far not been successful in developing countries. Of concern, more newborns died there after treatment with therapeutic hypothermia. Reasons for this include infections, which aggravate the consequences of the lack of oxygen. In order to develop a therapy that is effective in the context of infection-sensitized oxygen deficiency, the underlying pathophysiology must be better understood. As part of the DFG-funded project, we were able to show that the brain's own defense cells, microglial cells, play a significant role in infection-sensitized brain damage. We studied the time-dependent activation of microglial cells and were able to show that the NLRP3-inflammasome complex plays a central role in microglial activation. We were also able to show that NLRP3 activation occurs, among other things, through the binding of the CXCL1 ligand to the CXCR2 receptor. In the last step, we investigated the interaction of the peripheral immune response with microglial activation. Here we were able to show that neutrophilic granulocytes migrate into the brain time-dependently after a lack of oxygen and form networks there (neutrophil extracellular traps (NETs)). NET formation is visible early on, especially after therapeutic hypothermia, and could represent a mechanism of cooling therapy. In summary, we were able to show that microglia activation in the brain plays a central role in infection-sensitized oxygen deficiency, that the NLRP3 inflammation complex represents a central therapeutic target and that NETs are activated in the brain in a timedependent manner after acute oxygen deficiency. These results form the excellent basis for establishing new therapeutic approaches.
Publications
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Involvement of CXCL1/CXCR2 During Microglia Activation Following Inflammation-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Rats. Frontiers in Neurology, 11.
Serdar, Meray; Kempe, Karina; Herrmann, Ralf; Picard, Daniel; Remke, Marc; Herz, Josephine; Bendix, Ivo; Felderhoff-Müser, Ursula & Sabir, Hemmen
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Temporal Characterization of Microglia‐Associated Pro‐ and Anti‐Inflammatory Genes in a Neonatal Inflammation‐Sensitized Hypoxic‐Ischemic Brain Injury Model. Oxidative Medicine and Cellular Longevity, 2022(1).
Bernis, Maria E.; Schleehuber, Yvonne; Zweyer, Margit; Maes, Elke; Felderhoff-Müser, Ursula; Picard, Daniel & Sabir, Hemmen
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Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia. International Journal of Molecular Sciences, 24(4), 3598.
Bernis, Maria E.; Zweyer, Margit; Maes, Elke; Schleehuber, Yvonne & Sabir, Hemmen
