000K utf8 1100 2021$c2021-11-13 1500 eng 2050 urn:nbn:de:hbz:465-20230710-111534-3 2051 10.1186/s12974-021-02314-9 3000 Seitz, Marina 3010 Bendix, Ivo 3010 Dzietko, Mark 3010 Felderhoff-Müser, Ursula 3010 Herz, Josephine 3010 Köster, Christian 3010 Sabir, Hemmen 3010 Serdar, Meray 4000 Hypothermia modulates myeloid cell polarization in neonatal hypoxic-ischemic brain injury [Seitz, Marina] 4209 Background: Neonatal encephalopathy due to hypoxia–ischemia (HI) is a leading cause of death and disability in term newborns. Therapeutic hypothermia (HT) is the only recommended therapy. However, 30% still suffer from neurological deficits. Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation. In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice. Methods: Nine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia. Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature. Analyses were performed at 1, 3 and 7 days post HI. Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry. A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b + microglia/macrophages. Purity and composition of isolated cells was determined by flow cytometry. Results: Immediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI. Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT. However, ex vivo isolated CD11b + cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3. HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b + cells at day 1, which deteriorated until day 7 and was significantly decreased by HT. Conclusion: Our data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT. 4950 https://doi.org/10.1186/s12974-021-02314-9$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:hbz:465-20230710-111534-3$xR$3Volltext$534 4961 https://duepublico2.uni-due.de/receive/duepublico_mods_00077547 5051 610 5550 Hypothermia 5550 M1 M2 polarization 5550 Macrophages 5550 Microglia 5550 Myeloid cell polarization 5550 Neonatal hypoxia–ischemia