Active neurogenesis occurs throughout life and relies upon the proliferation, migration and proper differentiation of neural stem/progenitor cells (NPCs). Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia (HAD). In HAD, HIV-1-infected and immune-activated brain mononuclear phagocytes (MP;perivascular macrophages and microglia) drive central nervous system (CNS) inflammation and may alter normal neurogenesis. We previously demonstrated HIV-1-infected and activated MP inhibit neurogenesis, while enhancing astrogliogenesis in vitro and in vivo, through secretion of inflammatory cytokines such as IL-1b and TNF-a. Our preliminary study showed both IL-1b and TNF-a, as well as HIV-1-infected and LPS-activated MP induced STAT3 activation, a critical pathway of astrogliogenesis. Furthmore, microRNA-9 (miR-9) and brain-specific microRNA-124 (miR-124), factors shown to inhibit STAT3 activation, promote neuronal differentiation and inhibit astrocyte differentiation, are decreased in response to cytokine (IL-1b and TNF-a) treatment. Based on these observations, we hypothesize that HIV-1-infected and immune-activated MP promote NPC astrogliogenesis through secreted factors including cytokines (IL-1b and TNF-a) via the STAT3 pathway, and that miR-9 and miR-124 regulate this process through modulation of STAT3 activation. In this proposal, we will study the STAT3 pathway in NPCs following stimulation with inflammatory cytokines (including IL-1b and TNF-a) and HIV-1-infected and immune-activated MP and examine the effect on astrogliogenesis. We will also investigate the role of miRNAs (miR-9 and miR-124) in STAT3 activation and the modulation of human NPC differentiation mediated by cytokines (IL-1b and TNF-a) and HIV-1-infected and activated MP. We will test this hypothesis using a primary human NPC culture system and a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model. This research will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS. In addition, the work will also identify potential targets for therapeutic intervention for neural stem cell therapy.
Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia, in which HIV-1-infected and immune-activated macrophages drive central nervous system (CNS) inflammation. The study of the factors produced by these inflammatory cells and the signaling pathways involved in neural stem/progenitor cell differentiation will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS, and identify potential targets for therapeutic intervention for neural stem cell therapy.
| Chen, E; Xu, D; Lan, X et al. (2013) A novel role of the STAT3 pathway in brain inflammation-induced human neural progenitor cell differentiation. Curr Mol Med 13:1474-84 |
| Lan, Xiqian; Chen, Qiang; Wang, Yongxiang et al. (2012) TNF-? affects human cortical neural progenitor cell differentiation through the autocrine secretion of leukemia inhibitory factor. PLoS One 7:e50783 |
| Peng, Hui; Wu, Yumei; Duan, Zhiyuan et al. (2012) Proteolytic processing of SDF-1? by matrix metalloproteinase-2 impairs CXCR4 signaling and reduces neural progenitor cell migration. Protein Cell 3:875-82 |
| Zhu, Bing; Xu, Dongsheng; Deng, Xiaobei et al. (2012) CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway. Stem Cells 30:2571-83 |
| Peng, Hui; Sun, Lijun; Jia, Beibei et al. (2011) HIV-1-infected and immune-activated macrophages induce astrocytic differentiation of human cortical neural progenitor cells via the STAT3 pathway. PLoS One 6:e19439 |
