HSP70 potentiates interferon-alpha production by plasmacytoid dendritic cells: relevance for cutaneous lupus and vitiligo pathogenesis

Abstract

Background

Plasmacytoid dendritic cells (pDC) are a subset of DC specialized in the production of type I interferon (IFN-α/β) and involved in various cutaneous inflammatory and autoimmune disorders, such as cutaneous lupus (CLE) and vitiligo. Heat-Shock proteins (HSP) are molecular chaperones essential for maintaining cellular functions, but can act as a danger signal during inflammation.

Objectives

To decipher the role of HSP70 in the production of IFNα by pDC in CLE and vitiligo.

Methods

Expression of HSP70 and CD123⁺ pDC was analyzed by immunohistochemistry or immunofluorescence in CLE and vitiligo skin samples. Flow cytometry was performed to analyze expression of HSP70 receptors, activation markers on pDC and DNA uptake by pDC in the presence of HSP70. Impact of HSP70 on DNA-induced IFNα secretion by pDC was evaluated by enzyme-linked immunosorbent assay (ELISA). The effect of IFNα on CXCL9/10 gene and protein expression by keratinocytes was determined by real time PCR and ELISA.

Results

Infiltration of pDC in CLE and progressive vitiligo was primarily located in the epidermis, close to keratinocytes expressing HSP70. In vitro experiments revealed that pDC expressing HSP70 receptor LOX-1 were able to aggregate HSP70. Exogenous HSP70 induced activation of pDC and increased the uptake of exogenous DNA. Furthermore, HSP70 potentiated DNA-induced IFNα production by pDC. Lastly, IFNα induced expression of CXCL9 and CXCL10 by keratinocytes.

Conclusions

These data demonstrate that interaction between HSP70 and pDC in CLE and vitiligo is a prerequisite for the enhancement of IFNα production, and could be an interesting target.

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