Differential polarization between resident microglia and brain infiltrating macrophages in mouse models of Alzheimer's disease

Abstract

Human immunodeficiency virus type 1 (HIV-1) infects microglia and macrophages in the brain during seroconversion and eventually results in neuroinflammation and neurodegeneration in susceptible individuals. Inflammasomes are cytosolic protein complexes that serve as platforms for caspase-1 activation and ensuing cleavage and release of IL-1beta and IL-18. Our group recently showed that HIV-1 infection of human microglia induces the NLRP3 inflammasome. The viral protein R (Vpr) is an accessory protein encoded by HIV-1, which is essential for macrophage infection and is detected in serum and cerebrospinal fluid of HIV-infected patients. We investigated the actions of extracellular and intracellular Vpr expression on inflammasome activation in cells of monocytic lineage. Extracellular Vpr exposure to differentiated human monocytic cells (THP-1) and primary human microglia caused caspase-1 activation and reduced cell viability (p b 0.01). Vpr exposure also significantly increased transcription and secretion of IL-1beta and IL-18 (p b 0.001) although this effect was eliminated in THP-1 cells deficient in NLRP3. Infection of THP-1s and microglia with HIV-1 HxBruR−E+ (Vprdeficient) showed significantly reduced caspase-1 activation and IL1beta production (p b 0.01) compared to cells infected with HIV-1 HxBruRE (Vpr-encoding). To examine the effects of intracellular Vpr expression on inflammasome activation, THP-1 cells were transfected with Vpr, revealing enhanced caspase-1 activation and reduced cellular viability (p b 0.001) but without significant IL-1beta release. These observations indicated that extracellular Vpr activates the NLRP3 inflammasome by acting as both Signals 1 and 2. Thus, Vpr-induced NLRP3 inflammasome activation likely contributes to HIV-1 associated neuroinflammation.