TY - JOUR
T1 - Insulin-like growth factor 2 receptor is an IFNγ-inducible microglial protein that facilitates intracellular HIV replication
T2 - Implications for HIV-induced neurocognitive disorders
AU - Suh, Hyeon Sook
AU - Cosenza-Nashat, Melissa
AU - Choi, Namjong
AU - Zhao, Meng Liang
AU - Li, Jiu Feng
AU - Pollard, Jeffrey W.
AU - Jirtle, Randy L.
AU - Goldstein, Harris
AU - Lee, Sunhee C.
N1 - Funding Information:
Supported by National Institutes of Health grants K01 MH084705, RO1 MH55477, RO1 CA131270, PO1 CA100324 , Einstein CFAR P30 AI051519 , and a CFAR pilot grant.
PY - 2010/11
Y1 - 2010/11
N2 - Insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose 6-phosphate (M6P) receptor, is a transmembrane glycoprotein localized in the trans-Golgi region and is involved in targeting both M6P-bearing enzymes and IGF2 to the lysosomal compartment. During development, IGF2R plays a crucial role in removing excess growth factors from both tissue and blood. Due to the perinatal lethality of the global Igf2r knockout, the function of IGF2R in adults, particularly in the CNS, is not known. We made a novel observation that IGF2R is highly expressed in microglial nodules in human brains with HIV encephalitis. In vitro, microglial IGF2R expression was uniquely enhanced by IFNγ among the several cytokines and TLR ligands examined. Furthermore, in several in vitro models of HIV infection, including human and murine microglia, macrophages, and nonmacrophage cells, IGF2R is repeatedly shown to be a positive regulator of HIV infection. IGF2R RNAi also down-regulated the production of the IP-10 chemokine in HIV-infected human microglia. Injection of VSVg env HIV into mouse brain induced HIV p24 expression in neurons, the only cell type normally expressing IGF2R in the adult brain. Our results demonstrate a novel role for IGF2R as an inducible microglial protein involved in regulation of HIV and chemokine expression. Mice with the Csf1r- driven Igf2r knockout should be useful for the investigation of macrophage-specific IGF2R function.
AB - Insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose 6-phosphate (M6P) receptor, is a transmembrane glycoprotein localized in the trans-Golgi region and is involved in targeting both M6P-bearing enzymes and IGF2 to the lysosomal compartment. During development, IGF2R plays a crucial role in removing excess growth factors from both tissue and blood. Due to the perinatal lethality of the global Igf2r knockout, the function of IGF2R in adults, particularly in the CNS, is not known. We made a novel observation that IGF2R is highly expressed in microglial nodules in human brains with HIV encephalitis. In vitro, microglial IGF2R expression was uniquely enhanced by IFNγ among the several cytokines and TLR ligands examined. Furthermore, in several in vitro models of HIV infection, including human and murine microglia, macrophages, and nonmacrophage cells, IGF2R is repeatedly shown to be a positive regulator of HIV infection. IGF2R RNAi also down-regulated the production of the IP-10 chemokine in HIV-infected human microglia. Injection of VSVg env HIV into mouse brain induced HIV p24 expression in neurons, the only cell type normally expressing IGF2R in the adult brain. Our results demonstrate a novel role for IGF2R as an inducible microglial protein involved in regulation of HIV and chemokine expression. Mice with the Csf1r- driven Igf2r knockout should be useful for the investigation of macrophage-specific IGF2R function.
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U2 - 10.2353/ajpath.2010.100399
DO - 10.2353/ajpath.2010.100399
M3 - Article
C2 - 20889566
AN - SCOPUS:78149300900
SN - 0002-9440
VL - 177
SP - 2446
EP - 2458
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -