Amlexanox as a potential novel therapeutic option for SLE
Concept
In SLE, plasmacytoid dendritic cells produce type I interferon (IFN-I) in response to RNA- and DNA-containing immune complexes via activation of endosomal toll-like receptors 7 and 9. B cells are important players in SLE pathogenesis and are directly activated by the IFN-I protein and indirectly by IFN-I induced release of B cell activating factor (BAFF) by monocytes. The cytokine BAFF is essential for B cell activation, differentiation, and survival, and high serum BAFF levels have been associated with SLE disease activity. Although inhibition of both IFN-I and BAFF has been shown to have beneficial effects in clinical trials, such therapies do not relieve all patients from symptoms and complications. TANK-binding kinase 1 (TBK-1) is an important signalling hub leading to IFN-I production and subsequent induction of interferon stimulated genes such as BAFF.
Facts and Figures
A Björk
Karolinska Institute
albin.bjork@ki.se
Meet the Team
Erasmus MC
Final results
We showed that inhibition of Tank binding kinase-1 (TBK1) by amlexanox significantly lowered production of type I interferon (IFN) in PBMC cultures stimulated through nucleic acid sensing endosomal and cytosolic routes. Sorted B cells were co-cultured with feeder cells under germinal center-like conditions with CD40L, IL-21, and amlexanox at various concentrations. Using this system, we showed that inhibition of TBK1 by amlexanox resulted in significantly decreased differentiation into CD38highCD27highCD138+/- antibody secreting cells (ASCs). Correspondingly, proliferation of B cells and production of IgM and IgG was lower in the amlexanox condition. Using cells from patients with SLE, childhood-onset SLE, Sjögren’s syndrome and systemic sclerosis we showed that amlexanox diminished spontaneous expression of the type I IFN induced gene MX1, and inhibited B cell differentiation into ASCs. We conclude that inhibition of TBK1 is a promising therapeutic target for treatment of SLE warranting further investigations.
Lay Summary
There is a lack of effective treatments for SLE. In this project, we evaluated a drug called amlexanox and its effect on cells from healthy volunteers and patients with SLE, Sjögren’s syndrome, and systemic sclerosis.
In a large subset of the patients with SLE the production of a group of inflammatory proteins called interferons is permanently present. Interferons can be produced after activation of a molecule called TBK1. We therefore believe that faults in the immune system of SLE patients could potentially be treated by blocking the enzyme TBK1 using a drug called amlexanox.
B cells are important in the pathogenesis of SLE and can develop into antibody secreting cells (ASCs). In SLE, such cells produce autoantibodies which contribute to the disease partly by causing the production of interferon. Other researchers have recently shown that TBK1 plays an important role in B cells.
Using cell culture systems, we found that amlexanox inhibited production of interferon proteins. We isolated B cells from healthy donors, patients with SLE and other autoimmune diseases, and stimulated them to become ASCs. Addition of amlexanox to the B cell cultures resulted in inhibition of the cells, so that fewer B cells developed into ASCs. We confirmed this by measuring antibodies levels, which were lower when amlexanox had been added. The expression of an important interferon simulated gene was lowered if amlexanox was added to patient cells.
In all, these data show that inhibition of TBK1 by amlexanox may be a promising way to treat SLE.
Publications
- POS1428 Björk A, Wahadat MJ, Braams M, et al. AMLEXANOX INHIBITS PRODUCTION OF TYPE I INTERFERON AND SUPPRESSES B CELL DIFFERENTIATION AND IMMUNOGLOBULIN PRODUCTION IN VITRO: A POTENTIAL NOVEL THERAPEUTIC OPTION FOR SLE. Annals of the Rheumatic Diseases 2023;82:1068.
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