Background Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease characterized by hyperactivated immune responses to self and persistent systemic inflammation. In addition to autoreactive T and B cells, dendritic cells also play an important role in inducing inflammation. Previously, we have reported abnormalities in circulating and bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) from SLE patients which suggested that pDCs may play a role in mediating SLE pathogenesis1–3.
Objectives In this investigation, we aim to seek for potential regulators that mediate functional aberrations of pDCs in SLE.
Methods Bone marrow-derived pDCs from NZB/W F1 mice before and after the disease onset were compared for costimulatory molecule expressions and toll-like receptor (TLR) 7 stimulated responses. TLR7-induced microRNA (miRNA) profile changes in pDCs were examined to identify specific miRNA regulator. Functional validation of specific miRNA was further studied by transfection of miRNA mimics.
Results In vitro derivation of pDCs from BM of pre-symptomatic and symptomatic NZB/W F1 mice showed similar basal expression of co-stimulatory molecules and TLRs -7 and -9. Functionally, symptomatic pDCs exhibited hypersensitivity to TLR7 but not TLR9 stimulation, as represented by the elevated upregulation of CD40, CD86 and MHC class II molecules upon R837 stimulation. In miRNA profiling, a significantly higher induction of miR-155 in symptomatic pDCs following TLR7 stimulation was observed. The transfection of miR-155 mimics in pre-symptomatic pDCs induced an augmented expression of Cd40 which is consistent with the increased CD40 expression in symptomatic pDCs. Cd40 expression was also found to negatively correlate with the miR-155 target Ship1 in pDCs.
Conclusions Overall, results from the current study provide evidence for miR-155-mediated regulation in pDC functional abnormalities in SLE. Findings from this study contribute to a better understanding of SLE pathogenesis and ignite future interests in evaluating the molecular regulation in autoimmunity.
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Jin, O., et al., Abnormalities in circulating plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Arthritis research & therapy. 2010;12(4):R137
Nie, Y.J., et al, Phenotypic and functional abnormalities of bone marrow-derived dendritic cells in systemic lupus erythematosus. Arthritis research & therapy. 2010;12(3):R91.
Acknowledgement Hong Kong Research Grant Council General Research Fund (770213)
Disclosure of Interest None declared