title: Nicotinamide phosphoribosyltransferase/visfatin expression by inflammatory monocytes mediates arthritis pathogenesis.
abstract: OBJECTIVE
  Nicotinamide phosphoribosyltransferase (NAMPT)/pre-B-cell colony-enhancing factor/visfatin exerts multiple functions and has been implicated in the pathogenesis of rheumatoid arthritis. To gain insight into its role in arthritis and given that NAMPT is identified as a novel mediator of innate immunity, we addressed the function of monocyte-derived NAMPT in experimental arthritis by selective gene knockdown in inflammatory monocytes.
  
  
  METHODS
  siRNA uptake and NAMPT expression were determined in Ly6Chigh and Ly6Clow monocyte subsets following intravenous injection of siRNA against NAMPT (siNAMPT) or non-targeting siRNA (siCT) formulated with the DMAPAP cationic liposome into mice. Mice with established collagen-induced arthritis (CIA) were treated weekly after disease onset with siNAMPT or siCT and clinical features were assessed. T-helper cell frequencies, cytokine production and percentage of IL-6-producing Ly6Chigh monocytes were analysed. Using a co-culture system consisting of purified CD14 monocytes and autologous CD4 T cells, NAMPT and cytokine production, and the percentage of IL-17-producing CD4 T cells, were determined following transfection of CD14 monocytes with siCT or siNAMPT.
  
  
  RESULTS
  On intravenous injection, siRNA was preferentially engulfed by Ly6Chigh monocytes, and siRNA-mediated silencing of NAMPT expression in Ly6Chigh monocytes inhibited CIA progression. This effect was associated with reduced IL-6 production by Ly6Chigh monocytes, reduced proportion of Th17 cells and autoantibody titers, and decreased activation and infiltration of monocytes/macrophages and neutrophils in arthritic joints. Moreover, NAMPT-RNAi-silenced CD14 monocytes were found to reduce the percentage of IL-17-producing CD4 T cells in vitro.
  
  
  CONCLUSIONS
  Our results show that the expression of NAMPT in Ly6Chigh monocytes promotes many downstream effects involved in inflammatory arthritis and demonstrate the utility of targeting disease-causing genes, such as NAMPT, in Ly6Chigh monocytes for therapeutic intervention in arthritis.
authors: INSERM, U844, University Hospital Saint Eloi, Montpellier, France.
authors: Jessy
authors: J
authors: Présumey
authors: Gabriel
authors: G
authors: Courties
authors: Pascale
authors: P
authors: Louis-Plence
authors: Virginie
authors: V
authors: Escriou
authors: Daniel
authors: D
authors: Scherman
authors: Yves-Marie
authors: YM
authors: Pers
authors: Hans
authors: H
authors: Yssel
authors: Jérôme
authors: J
authors: Pène
authors: Diego
authors: D
authors: Kyburz
authors: Steffen
authors: S
authors: Gay
authors: Christian
authors: C
authors: Jorgensen
authors: Florence
authors: F
authors: Apparailly
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020868:Gene Silencing; D006801:Humans; D056747:Immunomodulation / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000276:immunology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D034741:RNA, Small Interfering; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C495867:nicotinamide phosphoribosyltransferase, mouse
keywords: Arthritis; Cytokines; Inflammation