Background Interferon I (IFN-I) signature is an important feature of systemic lupus erythematosus (SLE). Our previous study identified an IFN-I signature in both bone marrow (BM) and peripheral blood of SLE patients. The overlapping roles of IFNα subtypes and disappointing results with IFNα subtype blockade in clinical trials calls for alternative targets and recent findings centred on IFNβ suggest that it is an important candidate molecule in SLE. IFNβ has distinct features as compared to IFNα: higher affinity binding to the shared IFN-I receptors, IFNβ specific gene transcripts, induction of senescence in fibroblast. As a critical non-hematopoietic component in BM, MSCs create a microenvironment for hematopoiesis and immunity. MSCs display robust immunomodulatory properties. MSC defects have been suggested in autoimmune diseases. Taking into consideration the importance of IFNβ and MSCs in autoimmune diseases, here we set out to investigate the role of IFNβ and MSC in SLE pathogenesis, and the underlying mechanisms.

Materials and methods BM MSCs were isolated with FicollPaque gradient centrifugation (1.073 ± 0.001 g/ml) and phenotyped using flow cytometry. Various in vitro approaches including confocal immunofluorescence immunocytochemistry, real-time PCR, western blotting, comet assay, beta-galactosidase assay and RNA interference were applied.

Results We compared 6 age paired BM aspirates from healthy controls and SLE patients. SLE MSCs show reduced proliferation rate, increased production of reactive oxygen, and increased DNA damage and repair (DDR), which leads to p53 mediated senescence associate secretory phenotype (SASP) and inhibited immunomodulatory factors production. IFNβ increased 5 folds and IFNβ specific genes are significantly elevated (p < 0.05) in SLE BM MSCs and are closely correlated to the level of Mitochondrial Antiviral Signalling Protein (MAVS) (r > 0.9, p < 0.01), an intracytoplasmic nucleic acid sensor. Silencing MAVs inhibits IFNβ expression and reverses SASP in SLE MSCs.

Conclusions SLE is associated with elevated IFN-I in BM. BM MSCs produce IFNβ, have increased DDR and SASP. Thus an IFNβ positive feedback loop forms in SLE BM MSCs. By silencing MAVS, also named Interferon Beta Promoter Stimulator Protein 1, IFNβ expression is inhibited and IFNβ positive feedback loop is disrupted. Moreover, SASP is rescued by MAVs blockage in SLE BM MSCs. Our novel findings of the IFNβ positive feedback loop and related SASP in SLE BM MSCs shed light on SLE pathogenesis. In addition, our study has also revealed the essential role of MAVS in IFNβ positive loop, and thus provided a new potential therapeutic target for SLE treatment.