STAT3 and astrogliogenesis in HIV-1 associated dementia

University Of Nebraska Medical Center, Omaha NE

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Abstract

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.