title: Alteration of lysosome fusion and low-grade inflammation mediated by super-low-dose endotoxin.
abstract: Subclinical super-low-dose endotoxin LPS is a risk factor for the establishment of low-grade inflammation during the pathogenesis and progression of chronic diseases. However, the underlying mechanisms are not well understood. At the cellular level, a disruption of lysosome fusion with endosomes or autophagosomes may contribute to the potentiation of low-grade inflammation. In this study, we identified that subclinical super-low-dose endotoxin LPS can potently inhibit the process of endosome acidification and lysosome fusion with endosomes or autophagosomes in primary macrophages. Super-low-dose LPS induced the inhibitory phosphorylation of VPS34, thus leading to the disruption of endosome-lysosome fusion. This effect may depend upon the clearance and relocation of Tollip in macrophages by super-low-dose LPS. Consistent with this notion, Tollip-deficient macrophages had constitutively elevated levels of VPS34 inhibitory phosphorylation and constitutive disruption of endosome-lysosome fusion. By employing a skin excision wound-healing model, we observed that Tollip-deficient mice had significantly elevated levels of cell stress and reduced wound repair. This study reveals a novel mechanism responsible for the modulation of endosome-lysosome fusion and low-grade inflammation in innate macrophages.
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Bianca
authors.initials: B
authors.lastname: Baker
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Shuo
authors.initials: S
authors.lastname: Geng
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Na
authors.initials: N
authors.lastname: Diao
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Yuan
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Xiguang
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Sean
authors.initials: S
authors.lastname: Dougherty
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910.
authors.forename: Caroline
authors.initials: C
authors.lastname: Stephenson
authors.affiliation: the Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029, and.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: the Department of Medicine, National Jewish Health, Denver, Colorado 80206.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
authors.affiliation: From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910, lwli@vt.edu.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D011992:Endosomes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D008247:Lysosomes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C410602:TOLLIP protein, human
keywords: Cell Signaling; Endosome-Lysosome Fusion; Innate Immunity; Lipopolysaccharide (LPS); Low-grade Inflammation; Lysosome; Macrophage; Macrophages; Super-low-dose Endotoxin