HIV-1-infected and/or immune activated macrophages regulate astrocyte SDF-1 production through IL-1beta.
Stromal cell-derived factor 1 alpha (SDF-1alpha) 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-1beta following both viral and immune activation. The MCM-induced production of SDF-1 was prevented by IL-1beta receptor antagonist (IL-1Ra) and IL-1beta 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-1beta mRNA expression. These observations provide direct evidence that IL-1beta, 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.
Peng
Hui
H
Laboratory of Neurotoxicology, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68195-5880, USA.
Erdmann
Nathan
N
Whitney
Nicholas
N
Dou
Huangyu
H
Gorantla
Santhi
S
Gendelman
Howard E
HE
Ghorpade
Anuja
A
Zheng
Jialin
J
D015526:AIDS Dementia Complex / Q000276:immunology* / Q000821:virology; D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000821:virology; D001921:Brain / Q000276:immunology / Q000821:virology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012795:Sialoglycoproteins / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D017077:Culture Media, Conditioned; C515256:Cxcl12 protein, mouse; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D012795:Sialoglycoproteins