RMD open · 2025
Amlexanox inhibits production of type I interferon and suppresses B cell differentiation in vitro: a possible therapeutic option for systemic lupus erythematosus and other systemic inflammatory diseases.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Björk Albin, Wahadat Mohamed Javad, Sánchez-Blázquez Maria, Braams Merijn, Rip Jasper, van Tilburg Sander J, van Helden-Meeuwsen Cornelia G, Kamphuis Sylvia, van den Bosch Thierry P P, Brkic Zana, Versnel Marjan A
Аннотация
OBJECTIVES: Activation of the type I interferon (IFN) pathway and autoreactive B cells are key immunopathogenic features of systemic lupus erythematosus (SLE), primary Sjögren's disease (pSjD) and systemic sclerosis (SSc). TANK-binding kinase 1 (TBK1) is a mediator of type I IFN and essential during B cell development in mice. We investigated the properties of the TBK1 inhibitor amlexanox in systemic autoimmune diseases.
METHODS: The effects of amlexanox on peripheral blood mononuclear cells (PBMCs) stimulated with Imiquimod, CpG-A, Poly:IC, G3-YsD and 3p-hpRNA were assessed. B cells from healthy controls and patients with SLE, pSjD and SSc were cultured with CD40L, IL-21, IFN, B cell activating factor (BAFF) and amlexanox. Differentiation into CD38highCD27highCD138+/- cells, proliferation, and IgM and IgG production were measured.
RESULTS: Amlexanox inhibited production of type I IFN induced through endosomal and cytosolic routes in PBMCs. Likewise, supernatants from amlexanox-treated cells did not induce expression of BAFF and MX1. Amlexanox inhibited spontaneous MX1 expression in PBMCs from SLE, pSjD and SSc patients. Immunohistochemical staining confirmed expression of the TBK1 protein in pSjD salivary glands. Using a B cell differentiation assay, addition of amlexanox decreased B cell proliferation and differentiation into CD27highCD38highCD138+/- plasmablasts and plasma cells. Correspondingly, production of IgM and IgG was suppressed. The observations were corroborated in B cells from patients with SLE, pSjD and SSc.
CONCLUSIONS: Our findings demonstrate inhibitory effects of amlexanox on type I IFN production and B cell differentiation in primary human cells. Inhibition of TBK1 could potentially be a therapeutic option for the treatment of type I IFN-driven systemic inflammatory diseases.
METHODS: The effects of amlexanox on peripheral blood mononuclear cells (PBMCs) stimulated with Imiquimod, CpG-A, Poly:IC, G3-YsD and 3p-hpRNA were assessed. B cells from healthy controls and patients with SLE, pSjD and SSc were cultured with CD40L, IL-21, IFN, B cell activating factor (BAFF) and amlexanox. Differentiation into CD38highCD27highCD138+/- cells, proliferation, and IgM and IgG production were measured.
RESULTS: Amlexanox inhibited production of type I IFN induced through endosomal and cytosolic routes in PBMCs. Likewise, supernatants from amlexanox-treated cells did not induce expression of BAFF and MX1. Amlexanox inhibited spontaneous MX1 expression in PBMCs from SLE, pSjD and SSc patients. Immunohistochemical staining confirmed expression of the TBK1 protein in pSjD salivary glands. Using a B cell differentiation assay, addition of amlexanox decreased B cell proliferation and differentiation into CD27highCD38highCD138+/- plasmablasts and plasma cells. Correspondingly, production of IgM and IgG was suppressed. The observations were corroborated in B cells from patients with SLE, pSjD and SSc.
CONCLUSIONS: Our findings demonstrate inhibitory effects of amlexanox on type I IFN production and B cell differentiation in primary human cells. Inhibition of TBK1 could potentially be a therapeutic option for the treatment of type I IFN-driven systemic inflammatory diseases.