MicroRNA-155 Mediates Augmented CD40 Expression in Bone Marrow Derived Plasmacytoid Dendritic Cells in Symptomatic Lupus-Prone NZB/W F1 Mice

Abstract

Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease characterized by hyperactivated immune responses to self-antigens and persistent systemic inflammation. Previously, we reported abnormalities in circulating and bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) from SLE patients. Here, we aim to seek for potential regulators that mediate functional aberrations of pDCs in SLE. BM-derived pDCs from NZB/W F1 mice before and after the disease onset were compared for toll-like receptor (TLR) induced responses and microRNA profile changes. While pDCs derived from symptomatic mice were phenotypically comparable to pre-symptomatic ones, functionally they 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. Upregulated induction of miR-155 in symptomatic pDCs following TLR7 stimulation was observed. 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. Overall, our results 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.

Heightened TLR7/9-Induced IL-10 and CXCL13 Production with Dysregulated NF-ҝB Activation in CD11chiCD11b+ Dendritic Cells in NZB/W F1 Mice

“…Similarly, using the common mDCs markers CD11c and CD11b [26], a distinct population of CD11c hi CD11b + cells constitutively expressing high levels of MHC class II and the costimulatory molecule CD80 could be identified (Figure 1B). Using these markers, the frequency and total number of pDC and CD11c hi CD11b + mDC were compared in BWF1 mice before and after symptomatic SLE onset, which was marked by an increase in anti-dsDNA antibody level and the manifestation of proteinuria [27]. Results showed that there was a lower splenic pDCs frequency in symptomatic (Sym) mice when compared with pre-symptomatic (Pre-Sym) mice (0.48 ± 0.04% VS. 1.15 ± 0.06%, p ≤ 0.0001) (Figure 1C), while this difference was not observed in age- and sex-matched non-lupic parental NZW strain (Supplementary Figure S1).…”

“…These lines were maintained and interbred to generate F1 generation (BWF1) in the Minimal Disease Area of the Laboratory Animal Unit, The University of Hong Kong. Disease development in BWF1 was assessed by monitoring serum level of anti-dsDNA IgG and development of proteinuria, as previously described [27]. Mice between 8 and15 weeks old without an increase in anti-dsDNA IgG (level comparable to the non-lupus parental strain NZW) and negative for proteinuria were defined as pre-symptomatic mice, while mice above 20 weeks old with elevation of anti-dsDNA IgG (level higher than two standard deviations of mean serum level in NZW) and proteinuria development (3mg/mL or above) for at least two consecutive weeks were defined as symptomatic mice.…”

Dysregulation of Cell Death and Its Epigenetic Mechanisms in Systemic Lupus Erythematosus

“…Current studies have shown that dysregulated cell death contributes to SLE by increasing availability, pathogenic modifications, and abnormal processing and presenting of self-antigens. Epigenetic modifications involve this complex process at different levels, including triggering apoptosis at the initial phase, induction of impaired clearance of apoptotic materials by inappropriate DNA methylation, and aberrant antigen presentation or IFN-α production by DCs [ 93 ]. To induce the apoptosis of over-activated immune cells, recombinant PD-L1Ig has been proposed as a therapy in lupus [ 94 ].…”

The CD40-ATP-P2X7 Receptor Pathway: Cell to Cell Cross-Talk to Promote Inflammation and Programmed Cell Death of Endothelial Cells

“…Peripheral blood mononuclear cells from poorly controlled patients with type I diabetes exhibit increased mRNA levels of the functional type I isoform of CD40 (60). It is not known whether changes in micro RNA that control CD40 transcription [i.e., miR-155, miR-424, miR-503 (61,62)] explain the upregulation of CD40 mRNA. In addition, CD154 protein levels are elevated in the blood from patients with diabetic microangiopathy and mice with diabetes (7,63,64).…”