title: Heat shock protein 70 potentiates interferon alpha production by plasmacytoid dendritic cells: relevance for cutaneous lupus and vitiligo pathogenesis.
abstract: BACKGROUND
  Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells specialized in the production of type I interferon (IFN-α/β) and involved in various cutaneous inflammatory and autoimmune disorders, such as cutaneous lupus erythematosus (CLE) and vitiligo. Heat shock proteins (HSPs) are molecular chaperones essential for maintaining cellular functions, but they can act as a danger signal during inflammation.
  
  
  OBJECTIVE
  To decipher the role of HSP70 in the production of IFN-α by pDCs in CLE and vitiligo.
  
  
  METHODS
  Expression of HSP70 and CD123+pDCs was analysed by immunohistochemistry or immunofluorescence in CLE and vitiligo skin samples. Flow cytometry was performed to analyse expression of HSP70 receptors, activation markers on pDCs and DNA uptake by pDCs in the presence of HSP70. The impact of HSP70 on DNA-induced IFN-α secretion by pDCs was evaluated by enzyme-linked immunosorbent assay (ELISA). The effect of IFN-α on chemokine (C-X-C motif) ligand 9 (CXCL9)/10 gene and protein expression by keratinocytes was determined by real-time polymerase chain reaction and ELISA.
  
  
  RESULTS
  Infiltration of pDCs in CLE and progressive vitiligo was primarily located in the epidermis, close to keratinocytes expressing HSP70. In vitro experiments revealed that the pDCs expressing HSP70 receptor Lox-1 (lectin-like oxidized low-density lipoprotein-receptor-1) were able to aggregate HSP70. Exogenous HSP70 induced activation of pDCs and increased the uptake of exogenous DNA. Furthermore, HSP70 potentiated DNA-induced IFN-α production by pDCs. Finally, IFN-α induced expression of CXCL9 and CXCL10 by keratinocytes.
  
  
  CONCLUSIONS
  These data demonstrate that interaction between HSP70 and pDCs in CLE and vitiligo is a prerequisite for the enhancement of IFN-α production, and could be an interesting target.
authors.affiliation: INSERM U1035, BMGIC, Immuno-dermatology ATIP-AVENIR, Bordeaux, France.
authors.forename: C
authors.initials: C
authors.lastname: Jacquemin
authors.affiliation: AQUIDERM, Bordeaux, France.
authors.forename: J
authors.initials: J
authors.lastname: Rambert
authors.affiliation: Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, Bordeaux, France.
authors.forename: S
authors.initials: S
authors.lastname: Guillet
authors.affiliation: INSERM U1035, BMGIC, Immuno-dermatology ATIP-AVENIR, Bordeaux, France.
authors.forename: D
authors.initials: D
authors.lastname: Thiolat
authors.affiliation: INSERM U1035, BMGIC, Immuno-dermatology ATIP-AVENIR, Bordeaux, France.
authors.forename: N
authors.initials: N
authors.lastname: Boukhedouni
authors.affiliation: Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, Bordeaux, France.
authors.forename: M-S
authors.initials: MS
authors.lastname: Doutre
authors.affiliation: Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, Bordeaux, France.
authors.forename: A-S
authors.identifier: http://orcid.org/0000-0003-4034-0395
authors.initials: AS
authors.lastname: Darrigade
authors.affiliation: Department of Dermatology, AP-HP, Hôpital Henri-Mondor, Créteil, France.
authors.forename: K
authors.initials: K
authors.lastname: Ezzedine
authors.affiliation: CNRS/UMR 5164, Immuno ConcEpT, University of Bordeaux, Bordeaux, France.
authors.forename: P
authors.initials: P
authors.lastname: Blanco
authors.affiliation: INSERM U1035, BMGIC, Immuno-dermatology ATIP-AVENIR, Bordeaux, France.|Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, Bordeaux, France.
authors.forename: A
authors.initials: A
authors.lastname: Taieb
authors.affiliation: INSERM U1035, BMGIC, Immuno-dermatology ATIP-AVENIR, Bordeaux, France.
authors.forename: K
authors.initials: K
authors.lastname: Boniface
authors.affiliation: INSERM U1035, BMGIC, Immuno-dermatology ATIP-AVENIR, Bordeaux, France.|Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, Bordeaux, France.
authors.forename: J
authors.initials: J
authors.lastname: Seneschal
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis*; D015603:Keratinocytes / Q000378:metabolism; D008178:Lupus Erythematosus, Cutaneous / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D051217:Toll-Like Receptor 9 / Q000819:agonists; D014820:Vitiligo / Q000209:etiology*; D055815:Young Adult
chemical_list: C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018840:HSP70 Heat-Shock Proteins; D016898:Interferon-alpha; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9