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AB0123 Microrna-mediated regulations in plasmacytoid dendritic cells in lupus mice
  1. S. Yan1,
  2. V. S. F. Chan1,
  3. R. C. Y. Tam1,
  4. C. S. Lau1
  1. 1Department of Medicine, University of Hong Kong, Hong Kong, China

Abstract

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease complicated by the involvement of multiple organ systems and its diverse clinical manifestations. Typically, SLE patients have been characterised by the presence of anti-nuclear antibodies (ANA) and increased type I interferon (IFN) activities in their sera. Plasmacytoid dendritic cells (pDCs), also known as the most potent type I IFN-producing cells, are considered as the key pathogenic factor in SLE. Previous studies in the group have demonstrated abnormalities in circulating pDCs from SLE patients [1, 2]. Here, we aim to seek for the regulatory mechanisms of IFN productions by pDCs in SLE.

Objectives Hypothesising that the pDCs from an SLE origin are more responsive to TLR stimulations, the objective of this study is to find connections between regulatory factors such as microRNAs (miRNAs) and the aberrant pDC functions in SLE.

Methods The New Zealand Black/White (NZB/W) F1 mouse is a well-established lupus model as it spontaneously develops serum ANA followed by lupus nephritis and immune complex depositions in the kidneys. The mice were categorised into two groups based on their physiological status. Those with lupus symptoms such as high titres of serum ANA and persistent proteinuria were compared with the pre-symptomatic ones. Bone marrow (BM)-derived pDCs were generated with mouse Flt-3 ligand and then stimulated with toll-like receptor (TLR)-7 and TLR-9 agonists. Changes of their miRNA profiles upon stimulation were analysed by low-density arrays.

Results Pre-symptomatic and symptomatic mice have similar percentages of haematopoietic precursor cells in the bone marrow, which gave rise to comparable number of pDCs after eight days of culture. However, elevated TLR7 responses were observed in pDCs derived from BM of symptomatic mice, shown as the significantly heightened up-regulations of co-stimulatory markers CD40, CD86 and MHC class II. Results from the miRNA analysis revealed miRNA-155 as the most highly induced target, whose induction was consistently found higher in pDCs from the symptomatic mice.

Conclusions Results in this study concur with previous findings that, in human pDCs, miRNA-155 regulates the type I IFN productions and is itself inversely regulated by the IFN autocrine/paracrine dynamics [3]. Further investigations will focus on correlation of miRNA-155 up-regulation with the hyperactive pDCs in SLE using miRNA mimics and inhibitors. Together, our study sheds light on miRNA-mediated modulations in pDC abnormalities in SLE.

  1. Jin, O. et al. Abnormalities in circulating plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Arthritis research & therapy 12, R137 (2010).

  2. Nie, Y. J. et al. Phenotypic and functional abnormalities of bone marrow-derived dendritic cells in systemic lupus erythematosus. Arthritis research & therapy 12, R91 (2010).

  3. Zhou, H. et al. miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells. Blood 116, 5885–94 (2010).

Disclosure of Interest None Declared

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