HIV‐1‐infected and/or immune‐activated macrophage‐secreted TNF‐α affects human fetal cortical neural progenitor cell proliferation and differentiation

Abstract

Neurogenesis, tied to the proliferation, migration and differentiation of neural progenitor cells (NPC) is affected during neurodegenerative diseases, but how neurogenesis is affected during HIV-1 associated dementia (HAD) has not been fully addressed. Here we test the hypothesis that HIV-1-infected and/or immune-activated brain macrophages affect NPC proliferation and differentiation through the regulation of cytokines. We showed that human monocyte-derived macrophages (MDM) conditioned medium (MCM) induces a dose dependent increase in NPC proliferation. Conditioned media from lipopolysaccharide (LPS)-activated MDM (LPS-MCM) or HIV-infected MCM (HIV-MCM) induced a profound increase in NPC proliferation. HIV-infected and LPS-activated MCM (HIV+LPS-MCM) induced the most robust increase in NPC proliferation. Moreover, LPS-MCM and HIV+LPS-MCM decreased beta-III-tubulin and increased GFAP expression, demonstrating an induction of gliogenesis and inhibition of neurogenesis. The increase of NPC proliferation and gliogenesis correlated with increases in production of TNF-alpha by infected/activated MDM. Although both IL-1beta and TNF-alpha induced NPC proliferation and gliogenesis, these effects were only partially abrogated by soluble TNF-alpha receptors R1 and R2 (TNF-R1R2), but not by the IL-1 receptor antagonist (IL-1ra). This indicated that the HIV-1-infected/LPS-activated MCM-mediated effects were, in part, through TNF-alpha. These observations were confirmed in severe combined immunodeficient (SCID) mice with HIV-1 encephalitis (HIVE). In these HIVE mice, NPC injected with HIV-infected MDM showed more astrocyte differentiation and less neuronal differentiation compared to NPC injection alone. These observations demonstrated that HIV-1-infected and immune-activated MDM could affect neurogenesis through induction of NPC proliferation, inhibition of neurogenesis, and activation of gliogenesis.

HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway

“…3 E, F, 6). Although Tat inhibits astrocyte proliferation (Viscidi et al, 1989;Prakash et al, 2001;de la Fuente et al, 2002;Canani et al, 2003;Nyagol et al, 2006), Tat activates GFAP expression through a cascade of transcriptional network Zou et al, 2010;Fan et al, 2011Fan et al, , 2015. Thus, it is reasonable to assume that Tat-induced astrocytosis mainly results from increased GFAP expression.…”

“…For example, bone morphogenetic proteins promote dorsal neural formation in the brain (Liu and Niswander, 2005) and interface with several pathways, such as Stat3, Wnt, and Shh, to induce astrocyte specification (Stipursky and Gomes, 2007). Stat3 induces constitutive GFAP expression and Tat-activated GFAP expression (Fan et al, 2015) and promotes differentiation of neuron progenitors to astrocytes (Peng et al, 2011). Notch signaling also interfaces with Stat3 via Hes and promotes astrocyte differentiation (Bonni et al, 1997;Kamakura et al, 2004).…”

“…Next, NPC migration was assessed in the presence of conditioned media or recombinant Tat protein. Considering the finding that HIV-1 Tat inhibits cell proliferation (Viscidi et al, 1989;Prakash et al, 2001;, which may not allow us to distinguish Tat-impaired NPC migration from Tat-induced inhibition of NPC proliferation, we treated neurospheres first with mitomycin C to inhibit neurosphere proliferation (Shikatani et al, 2012) and then with Tat-containing conditioned media, and determined Tat effects on the neurosphere migration. Conditioned medium from Dox-induced iTat mouse primary astrocytes showed a significantly shorter NPC migration distance than that from Doxinduced WT mouse primary astrocytes (Fig.…”

“…In the era of combination antiretroviral therapy (cART), minor cognitive and motor disorder (MCMD) has become increasingly prevalent (Ellis et al, 1997;Kaul et al, 2001Kaul et al, , 2005. Impaired neurogenesis has been noted in the hippocampus of HIV-infected individuals, simian immunodeficiency virus-infected macaques, and severe combined immunodeficiency mice injected with HIV-infected human macrophages/microglia (Krathwohl and Kaiser, 2004a,b;Poluektova et al, 2005;Curtis et al, 2014). Several putative mechanisms are proposed for HIV-impaired neurogenesis.…”

“…Several putative mechanisms are proposed for HIV-impaired neurogenesis. HIV infection of macrophages/microglia and astrocytes alters expression of cytokines or growth factors Vallières et al, 2002;Sairanen et al, 2005;Iosif et al, 2006;Peng et al, 2008), several of which are known to affect adult hippocampal neurogenesis. HIV could have effects on NPCs through direct infection (Lawrence et al, 2004;Schwartz and Major, 2006;Whitney et al, 2009).…”