Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage

We show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain’s myeloid cells for the treatment of ICH.本研究表明，脑室内给予重组人脑多巴胺神经营养因子（recombinant human cerebral dopamine neurotrophic factor, rhCDNF）可加速胶原酶诱导的脑出血（intracerebral hemorrhage, ICH）动物模型的出血性病灶消退，减轻病灶周围水肿，并改善神经功能预后。本研究进一步证实，CDNF可作用于出血纹状体中的小胶质细胞/巨噬细胞，通过上调清道夫受体表达、增强红细胞吞噬作用、增加抗炎介质生成，同时抑制促炎细胞因子的产生。给予rhCDNF可上调血肿周围区域的Nrf2-HO-1通路，缓解氧化应激与未折叠蛋白反应。最终，本研究证实静脉给予rhCDNF对ICH动物模型具有有益作用，且全身给药可促进大脑髓系细胞的吞噬清除功能，用于治疗脑出血。