HIV‐1‐infected and/or immune activated macrophages regulate astrocyte SDF‐1 production through IL‐1β

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Abstract
Stromal cell‐derived factor 1 alpha (SDF‐1α) and its receptor CXCR4 play important roles in the pathogenesis of human immunodeficiency virus type one (HIV‐1)‐associated dementia (HAD) by serving as a HIV‐1 co‐receptor and affecting cell migration, virus‐mediated neurotoxicity, and neurodegeneration. However, the underlying mechanisms regulating SDF‐1 production during disease are not completely understood. In this report we investigated the role of HIV‐1 infected and immune competent macrophage, the principal target cell and mediator of neuronal injury and death in HAD, in regulating SDF‐1 production by astrocytes. Our data demonstrated that astrocytes are the primary cell type expressing SDF‐1 in the brain. Immune‐activated or HIV‐1‐infected human monocyte‐derived‐macrophage (MDM) conditioned media (MCM) induced a substantial increase in SDF‐1 production by human astrocytes. This SDF‐1 production was directly dependent on MDM IL‐1β following both viral and immune activation. The MCM‐induced production of SDF‐1 was prevented by IL‐1β receptor antagonist (IL‐1Ra) and IL‐1β siRNA treatment of human MDM. These laboratory observations were confirmed in severe combined immunodeficient (SCID) mice with HIV‐1 encephalitis (HIVE). In these HIVE mice, reactive astrocytes showed a significant increase in SDF‐1 expression, as observed by immunocytochemical staining. Similarly, SDF‐1 mRNA levels were increased in the encephalitic region as measured by real time RT‐PCR, and correlated with IL‐1β mRNA expression. These observations provide direct evidence that IL‐1β, produced from HIV‐1‐infected and/or immune competent macrophage, induces production of SDF‐1 by astrocytes, and as such contribute to ongoing SDF‐1 mediated CNS regulation during HAD.

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