Human SLE bone marrow mesenchymal stem cells (BMSCs) have a senescence-associated secretory phenotype (SASP) mediated by a MAVS-IFNβ feedback loop

Objective - BMSCs create a special microenvironment for hematopoiesis and immunity and also display robust immunomodulatory properties which are impaired in SLE. This study was undertaken to define the mechanisms of defects in human SLE BMSCs. Methods - Patients fulfilling SLE classification criteria and healthy controls were recruited under an Institutional Review Board approved protocol (n=6 each). BMSCs were isolated with low density Ficoll/Hypaque. BMSCs were verified by flow cytometry and studied using immunocytochemistry, real-time PCR, western blotting, comet assay, beta-galactosidase assay, and RNA interference. Results - SLE BMSCs have a senescent phenotype characterized by reduced proliferation rate, increased production of reactive oxygen species (ROS), increased DNA damage and repair, increased expression of p53 and p16 which block the cell cycle, and altered cytokine production (increased pro-inflammatory cytokine and decreased immunomodulatory cytokine production). Moreover, SLE BMSCs have a 5 fold increase in IFNβ (p  0.9, p < 0.01). Since MAVS is known to induce IFNβ production, we hypothesized a positive feedback loop between MAVS and IFNβ. Strikingly, silencing MAVS markedly decreased IFNβ, p53, and p16 protein levels and expression of mRNAs for pro-inflammatory cytokines. Conclusions - This study demonstrates a novel pathway for elevated IFNβ signaling in SLE that is not dependent on stimulation by immune complexes but rather is cell-intrinsic and critically mediated by IFNβ and MAVS, implicating new pathways as potential therapeutic targets. This article is protected by copyright. All rights reserved.