Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Bone marrow mesenchymal stromal cells (MSCs) are multipotent stem cells that create a special microenvironment for hematopoiesis and immunity. MSCs display robust immunomodulatory properties and transplantation of human MSC significantly improves nephritis in murine models of lupus. Immunomodulation by MSCs from lupus patients appears to be impaired, but the mechanisms underlying this defect is unknown. Our previous studies identified an IFN-I signature in SLE bone marrow (BM) and peripheral blood. In fibroblasts, prolonged treatment with IFNb, but not IFNα, has been shown to induce senescence through activation of reactive oxygen species (ROS), ATM and p53 DNA damage and repair (DDR) pathways. Here we investigate whether human SLE MSCs undergo senescence, the potential role of IFNb as a mediator in the SLE BM, and the implications for SLE pathogenesis.
Methods: SLE patients fulfilling ACR classification criteria and healthy controls were recruited under an IRB approved protocol (n=6 each). BM MSCs were isolated with low density Ficoll/Hypaque (1.073 g/ml) and grown in tissue culture. MSC phenotype was verified by flow cytometry. MSCs were studied using immunocytochemistry, real-time PCR, western blotting, comet assay for DNA damage, beta-galactosidase assay and RNA interference.
Results: The expression of IFNb was increased 5 folds (p<0.05) and IFNβ specific genes were significantly elevated in SLE MSCs. In addition, SLE MSCs displayed significantly reduced proliferation rate, increased production of ROS, increased DDR, and senescence associate secretory phenotype (SASP) as evidenced by increased cytokine production (all p<0.05): IL6 (4x), IL8 (8x), GRO1(9x), MCP2 (7x), RANTE1 (5x), GM-CSF (7x). The expression of immunomodulatory factors was significantly reduced (all p < 0.05): TGFβ (4x), IDO1 (3x) and LIF (10x). To begin to explore the signalling pathways that may mediate IFNB activation and DNA damage, we examined the level of Mitochondrial Antiviral Signaling Protein (MAVS), an intracytoplasmic nucleic acid sensor (also known as Interferon Beta Promoter Stimulator Protein 1). MAVS was positively correlated with the level of IFNb (r > 0.9, p< 0.01)， and strikingly, silencing MAVs inhibited IFNb expression and reversed the SASP in SLE MSCs.
Conclusion: The relative contribution of IFNα vs. IFNb to SLE disease pathogenesis remains unclear. IFNb has distinct features as compared to IFNα with higher affinity binding to IFN-I receptors, distinct gene transcripts and induction of senescence in fibroblasts. Our current data suggest that SLE BM MSCs produce IFNb, have increased ROS, DDR and SASP, decreased production of immunomodulatory factors, and elevated levels of MAVS. As a key regulator of IFNb expression, the expression of MAVS is highly correlated with the expression of IFNb. In addition, silencing MAVS disrupts IFNb production and rescues SASP in SLE MSCs. Our novel findings of an IFNb positive feedback loop and related SASP in SLE BM MSCs highlight a novel role for IFNb activation in SLE pathogenesis. Moreover, the essential role of MAVS in the IFNb positive feedback loop suggests dysregulated intracytoplasmic nucleic acid sensing and potential novel therapeutic targets for SLE treatment.
To cite this abstract in AMA style:Gao L, Anolik JH, Looney RJ. Increased Interferon b Expression in Bone Marrow Mediates a Senescent Phenotype and Impaired Production of Immunomodulatory Factors By SLE Mesenchymal Stromal Cells [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/increased-interferon-b-expression-in-bone-marrow-mediates-a-senescent-phenotype-and-impaired-production-of-immunomodulatory-factors-by-sle-mesenchymal-stromal-cells/. Accessed November 23, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-interferon-b-expression-in-bone-marrow-mediates-a-senescent-phenotype-and-impaired-production-of-immunomodulatory-factors-by-sle-mesenchymal-stromal-cells/