BACE1 is a novel regulator of Th17 function in EAEHernandez Mir, Gerard (2017) BACE1 is a novel regulator of Th17 function in EAE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractTh17 cells are implicated in autoimmune disease, including attack of the central nervous system (CNS) in multiple sclerosis. β-site APP-cleaving enzyme 1 (BACE1) is a membrane protease expressed in neurons and astrocytes. BACE1 is best known for its role in promoting neurodegeneration in Alzheimer’s disease by cleaving amyloid precursor protein, although it also plays a critical role in driving myelination of the central and peripheral nervous system. In addition, Here, we show that in vitro-differentiated BACE1-/- Th17 cells exhibited reduced IL-17A and CD73 production despite regular RORγt upregulation. Expression of IL-17F was mildly reduced while other prototypic Th17 molecules remained unaltered, such as RORγt, IL-23R or GM-CSF. BACE1 regulation of IL-17A and CD73 occurred in a T cell intrinsic manner and its Mechanistically, BACE1-deficiency resulted in reduced expression of PTEN and increased production of cAMP by the adenylate cyclase (AC). Concomitantly with imbalanced PTEN, BACE1-/- T cells exhibited higher phosphorylation of Akt upon T cell activation. Accordingly, forskolin-induced activation of the AC as well as PTEN hemideletion or pharmacological blockade phenocopied the findings observed in BACE1-/- Th17 cells. In summary, our data demonstrate that BACE1 is a novel regulator of Th17 function but does not impact Th17 differentiation. By modulating cAMP and PTEN levels, BACE1 can couple early signaling events, such as T cell activation and Ca2+ signaling, with the specific regulation of IL-17A and CD73 expression in Th17 cells. These findings highlight BACE1 as a novel potential therapeutic target to treat IL-17A-driven autoimmune disorders. Share
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