Insulin-like growth factor 2 receptor is an IFNgamma-inducible microglial protein that facilitates intracellular HIV replication: implications for HIV-induced neurocognitive disorders.
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.
Suh
Hyeon-Sook
HS
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. hyeon-sook.suh@einstein.yu.edu
Cosenza-Nashat
Melissa
M
Choi
Namjong
N
Zhao
Meng-Liang
ML
Li
Jiu-feng
JF
Pollard
Jeffrey W
JW
Jirtle
Randy L
RL
Goldstein
Harris
H
Lee
Sunhee C
SC
D015526:AIDS Dementia Complex / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000821:virology; D001921:Brain / Q000166:cytology / Q000473:pathology / Q000821:virology; D002460:Cell Line; D002478:Cells, Cultured; D006678:HIV / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D015658:HIV Infections / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D034622:RNA Interference; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000648:ultrastructure; D014779:Virus Replication
D017527:Receptor, IGF Type 2; D007371:Interferon-gamma