title: Macropinocytosis and TAK1 mediate anti-inflammatory to pro-inflammatory macrophage differentiation by HIV-1 Nef.
abstract: Macrophages (MΦ) are functionally classified into two types, anti-inflammatory M2 and pro-inflammatory M1. Importantly, we recently revealed that soluble HIV-1 proteins, particularly the pathogenetic protein Nef, preferentially activate M2-MΦ and drive them towards an M1-like MΦ, which might explain the sustained immune activation seen in HIV-1-infected patients. Here, we show that the preferential effect of Nef on M2-MΦ is mediated by TAK1 (TGF-β-activated kinase 1) and macropinocytosis. As with MAP kinases and NF-κB pathway, Nef markedly activated TAK1 in M-CSF-derived M2-MΦ but not in GM-CSF-derived M1-MΦ. Two Nef mutants, which were unable to activate MAP kinases and NF-κB pathway, failed to activate TAK1. Indeed, the TAK1 inhibitor 5Z-7-oxozeaenol as well as the ectopic expression of a dominant-negative mutant of TAK1 or TRAF2, an upstream molecule of TAK1, inhibited Nef-induced signaling activation and M1-like phenotypic differentiation of M2-MΦ. Meanwhile, the preferential effect of Nef on M2-MΦ correlated with the fact the Nef entered M2-MΦ more efficiently than M1-MΦ. Importantly, the macropinosome formation inhibitor EIPA completely blocked the internalization of Nef into M2-MΦ. Because the macropinocytosis activity of M2-MΦ was higher than that of M1-MΦ, our findings indicate that Nef enters M2-MΦ efficiently by exploiting their higher macropinocytosis activity and drives them towards M1-like MΦ by activating TAK1.
authors.affiliation: Center for AIDS Research, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Center for AIDS Research, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nasser
authors.affiliation: Center for AIDS Research, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Chihara
authors.affiliation: Center for AIDS Research, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Suzu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010873:Pinocytosis; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D020930:MAP Kinase Kinase Kinases; D015025:Zearalenone; D054311:nef Gene Products, Human Immunodeficiency Virus; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C514837:nef protein, Human immunodeficiency virus 1