title: Soluble alpha-enolase activates monocytes by CD14-dependent TLR4 signalling pathway and exhibits a dual function.
abstract: Rheumatoid arthritis (RA) is the most common form of chronic inflammatory rheumatism. Identifying auto-antigens targeted by RA auto-antibodies is of major interest. Alpha-enolase (ENO1) is considered to be a pivotal auto-antigen in early RA but its pathophysiologic role remains unknown. The main objective of this study was to investigate the in vitro effects of soluble ENO1 on peripheral blood mononuclear cells (PBMC) from healthy donors and RA patients in order to determine the potential pathogenic role of ENO1. ELISA, transcriptomic analysis, experiments of receptor inhibition and flow cytometry analysis were performed to determine the effect, the target cell population and the receptor of ENO1. We showed that ENO1 has the ability to induce early production of pro-inflammatory cytokines and chemokines with delayed production of IL-10 and to activate the innate immune system. We demonstrated that ENO1 binds mainly to monocytes and activates the CD14-dependent TLR4 pathway both in healthy subjects and in RA patients. Our results establish for the first time that ENO1 is able to activate in vitro the CD14-dependent TLR4 pathway on monocytes involving a dual mechanism firstly pro-inflammatory and secondly anti-inflammatory. These results contribute to elucidating the role of this auto-antigen in the pathophysiologic mechanisms of RA.
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Guillou
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.|Rouen University Hospital, Department of Rheumatology, Rouen, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Fréret
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Fondard
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Derambure
authors.affiliation: Rouen University Hospital, Department of Rheumatology, Rouen, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Avenel
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.|Rouen University Hospital, Department of Dermatology, Rouen, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Golinski
authors.affiliation: Rouen University Hospital, Department of Rheumatology, Rouen, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Verdet
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.|Rouen University Hospital, Department of Immunology, Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.|Rouen University Hospital, Department of Dermatology, Rouen, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Caillot
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.|Rouen University Hospital, Department of Dermatology, Rouen, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Musette
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.|Rouen University Hospital, Department of Rheumatology, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lequerré
authors.affiliation: INSERM, U905 &Normandy University, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.|Rouen University Hospital, Department of Rheumatology, Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Vittecoq
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C508609:IL10 protein, human; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; C439524:TNF protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D016753:Interleukin-10; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase