Serdar Meray, Kempe Karina, Herrmann Ralf, Picard Daniel, Remke Marc, Herz Josephine, Bendix Ivo, Felderhoff-Müser Ursula, Sabir Hemmen
Department of Pediatrics I/Neonatology and Experimental Perinatal Neurosciences, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Front Neurol. 2020 Oct 6;11:540878. doi: 10.3389/fneur.2020.540878. eCollection 2020.
Microglia are key mediators of inflammation during perinatal brain injury. As shown experimentally after inflammation-sensitized hypoxic ischemic (HI) brain injury, microglia are activated into a pro-inflammatory status 24 h after HI involving the NLRP3 inflammasome pathway. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been shown to be involved in NLRP3 activation, although their specific role during perinatal brain injury remains unclear. In this study we investigated the involvement of CXCL1/CXCR2 in brain tissue and microglia and brain tissue after inflammation-sensitized HI brain injury of newborn rats. Seven-day old Wistar rat pups were either injected with vehicle (NaCl 0.9%) or lipopolysaccharide (LPS), followed by left carotid ligation combined with global hypoxia (8% O for 50 min). Pups were randomized into four different treatment groups: (1) Sham group ( = 21), (2) LPS only group ( = 20), (3) Veh/HI group ( = 39), and (4) LPS/HI group ( = 42). Twenty-four hours post hypoxia transcriptome and gene expression analysis were performed on isolated microglia cells in our model. Additionally protein expression was analyzed in different brain regions at the same time point. Transcriptome analyses showed a significant microglial upregulation of the chemokine CXCL1 and its receptor CXCR2 in the LPS/HI group compared with the other groups. Gene expression analysis showed a significant upregulation of CXCL1 and NLRP3 in microglia cells after inflammation-sensitized hypoxic-ischemic brain injury. Additionally, protein expression of CXCL1 was significantly upregulated in cortex of male pups from the LPS/HI group. These results indicate that the CXCL1/CXCR2 pathway may be involved during pro-inflammatory microglia activation following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats. This may lead to new treatment options altering CXCR2 activation early after HI brain injury.
小胶质细胞是围产期脑损伤期间炎症的关键介质。如在炎症致敏的缺氧缺血性（HI）脑损伤后的实验所示，小胶质细胞在HI后24小时被激活进入促炎状态，涉及NLRP3炎性小体途径。趋化因子（C-X-C基序）配体1（CXCL1）及其同源受体CXCR2已被证明参与NLRP3激活，尽管它们在围产期脑损伤中的具体作用仍不清楚。在本研究中，我们调查了CXCL1/CXCR2在新生大鼠炎症致敏的HI脑损伤后脑组织、小胶质细胞和脑组织中的作用。7日龄的Wistar大鼠幼崽要么注射赋形剂（0.9%氯化钠）要么注射脂多糖（LPS），随后进行左颈动脉结扎并联合全身缺氧（8%氧气，持续50分钟）。幼崽被随机分为四个不同的治疗组：（1）假手术组（n = 21），（2）仅LPS组（n = 20），（3）赋形剂/HI组（n = 39），和（4）LPS/HI组（n = 42）。在缺氧后24小时对我们模型中分离的小胶质细胞进行转录组和基因表达分析。此外，在同一时间点对不同脑区的蛋白质表达进行分析。转录组分析显示，与其他组相比，LPS/HI组中小胶质细胞趋化因子CXCL1及其受体CXCR2显著上调。基因表达分析显示，在炎症致敏的缺氧缺血性脑损伤后，小胶质细胞中CXCL1和NLRP3显著上调。此外，LPS/HI组雄性幼崽皮质中CXCL1的蛋白质表达显著上调。这些结果表明，CXCL1/CXCR2途径可能参与新生大鼠炎症致敏的缺氧缺血性脑损伤后促炎性小胶质细胞的激活。这可能会带来新的治疗选择，在HI脑损伤后早期改变CXCR2的激活。
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