Microglia-derived CCL20 deteriorates neurogenesis following intraventricular hemorrhage

• Published in: Experimental neurology Vol. 370; p. 114561
• Main Authors: Yao, Nan, Li, Yulin, Han, Jinrui, Wu, Siting, Liu, Xin, Wang, Qiuyu, Li, Zhiguo, Shi, Fu-Dong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-12-2023
• Subjects: CCL20; Intraventricular hemorrhage; Microglia; Neurogenesis; Subventricular zone injury; Intraventricular hemorrhage; Subventricular zone injury; CCL20; Neurogenesis; Microglia
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2023.114561

Intraventricular hemorrhage (IVH) commonly occurs as an extension of intracerebral hemorrhage (ICH) into the brain ventricular system, leading to worse outcomes without effective management. Using a mouse model of IVH, we found that impaired neurogenesis is evident in the subventricular zone (SVZ), along with persistent microglia activation, leukocyte infiltration and cell death. Pharmacological depletion of microglia using PLX3397, an inhibitor of colony stimulating factor 1 receptor (CSF1R), promotes neurogenesis, and alleviated delayed functional impairments in IVH mice. Meanwhile, an elevated level of microglia-derived CC chemokine ligand 20 (CCL20) is observed in the SVZ following IVH, which can induce the upregulation of pro-inflammatory factors in microglia and impair the proliferation and survival of neural stem cells (NSCs) in vitro. Blocking CCL20 in microglia leads to downregulation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/the nuclear factor-κB (NF-κB) signaling pathway, which may contribute to CCL20-dependent pro-inflammatory responses and neural injury. These findings demonstrate a detrimental role of microglia in the neurogenesis and neurorepair after IVH in which CCL20 likely plays a role.
•The impaired neurogenesis was observed in the subventricular zone (SVZ) following IVH.•Persistent neuroinflammation, especially microglial activation within the SVZ, exacerbated neurogenesis impairment and neurodeficits in IVH mice.•The upregulation of CCL20 in microglia facilitated the secretion of pro-inflammatory cytokines and disrupted the proliferation and survival of NSCs.•Blocking CCL20 in the cultured microglia leads to downregulation of Akt/mTOR /NF-κB signaling pathway.