title: Glia maturation factor-γ negatively modulates TLR4 signaling by facilitating TLR4 endocytic trafficking in macrophages.
abstract: TLR4 signaling must be tightly regulated to provide both effective immune protection and avoid inflammation-induced pathology. Thus, the mechanisms that negatively regulate the TLR4-triggered inflammatory response are of particular importance. Glia maturation factor-γ (GMFG), a novel actin depolymerization factor/cofilin superfamily protein that is expressed in inflammatory cells, has been implicated in mediating neutrophil and T cell migration, but its function in macrophage immune response remains unclear. In the current study, the role of GMFG in the LPS-induced TLR4-signaling pathway was investigated in THP-1 macrophages and human primary macrophages. LPS stimulation of macrophages decreased GMFG mRNA and protein expression. We show that GMFG negatively regulates LPS-induced activation of NF-κB-, MAPK-, and IRF3-signaling pathways and subsequent production of proinflammatory cytokines and type I IFN in human macrophages. We found that endogenous GMFG localized within early and late endosomes. GMFG knockdown delayed LPS-induced TLR4 internalization and caused prolonged TLR4 retention at the early endosome, suggesting that TLR4 transport from early to late endosomes is interrupted, which may contribute to enhanced LPS-induced TLR4 signaling. Taken together, our findings suggest that GMFG functions as a negative regulator of TLR4 signaling by facilitating TLR4 endocytic trafficking in macrophages.
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Wulin
authors.initials: W
authors.lastname: Aerbajinai
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.forename: Kyung
authors.initials: K
authors.lastname: Chin
authors.forename: Griffin P
authors.initials: GP
authors.lastname: Rodgers
mesh_terms: D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020904:Glia Maturation Factor / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
chemical_list: D020904:Glia Maturation Factor; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C117487:glia maturation factor gamma