MiR-30a-3p Negatively Regulates BAFF Synthesis in Systemic Sclerosis and Rheumatoid Arthritis Fibroblasts

Abstract

We evaluated micro (mi) RNA-mediated regulation of BAFF expression in fibroblasts using two concomitant models: (i) synovial fibroblasts (FLS) isolated from healthy controls (N) or Rheumatoid Arthritis (RA) patients; (ii) human dermal fibroblasts (HDF) isolated from healthy controls (N) or Systemic Sclerosis (SSc) patients. Using RT-qPCR and ELISA, we first showed that SScHDF synthesized and released BAFF in response to Poly(I:C) or IFN-γ treatment, as previously observed in RAFLS, whereas NHDF released BAFF preferentially in response to IFN-γ. Next, we demonstrated that miR-30a-3p expression was down regulated in RAFLS and SScHDF stimulated with Poly(I:C) or IFN-γ. Moreover, we demonstrated that transfecting miR-30a-3p mimic in Poly(I:C)- and IFN-γ-activated RAFLS and SScHDF showed a strong decrease on BAFF synthesis and release and thus B cells survival in our model. Interestingly, FLS and HDF isolated from healthy subjects express higher levels of miR-30a-3p and lower levels of BAFF than RAFLS and SScHDF. Transfection of miR-30a-3p antisense in Poly(I:C)- and IFN-γ-activated NFLS and NHDF upregulated BAFF secretion, confirming that this microRNA is a basal repressors of BAFF expression in cells from healthy donors. Our data suggest a critical role of miR-30a-3p in the regulation of BAFF expression, which could have a major impact in the regulation of the autoimmune responses occurring in RA and SSc.

Unfolding the pathogenesis of scleroderma through genomics and epigenomics

“…Instead there are 3 studies that focused on how miRNAs were involved in immune mediators’ effect on dermal fibroblasts [91, 121, 122]. Nakashima et al showed that IL-17A exert its’ anti-fibrotic effect through upregulation of miR-129-5p that downregulated COL1A1 [122].…”

Epigenetic mechanisms: An emerging role in pathogenesis and its therapeutic potential in systemic sclerosis

“…MiR-30a-3p was found to be a basic repressor of B cell-activating factor (BAFF) expression in SSc fibroblasts by Alsaleh et al; while BAFF is an important factor for B cell activation, and BAFF is overexpressed in SSc. This suggests a potential anti-fibrotic effect of miR-30a-3p (Alsaleh et al, 2014). While miR-21 was significantly upregulated in SSc fibroblasts and regulated by TGF-␤, the overexpression of miR-21 can decrease the levels of Smad7, thereby implying its therapeutic role in SSc (Zhu et al, 2013).…”

The Versatile Role of microRNA-30a in Human Cancer

“…In addition, miR-30a played a crucial role in the regulation of the autoimmune responses in rheumatoid arthritis and systemic sclerosis by blocking B cell-activating factor [50]. Moreover, miR-30a could inhibit IL-10-induced cytokine release by targeting STAT1/ MD-2(a 25kDa lipopolysaccharide-binding protein) in human monocytes [51].…”