Apremilast Regulates the Teff/Treg Balance to Ameliorate Uveitis via PI3K/AKT/FoxO1 Signaling Pathway

Abstract

Autoimmune uveitis (AU), being one of the sight-threatening ocular inflammatory disorders, has been widely regarded by ophthalmologists and immunologists as a great challenge. Apremilast, a phosphodiesterase-4 inhibitor (PDE4i), which was approved by the U.S. Food and Drug Administration (FDA) for the treatment of active psoriatic arthritis in 2014, has been attracting researchers, who are exploring its efficiency and mechanism on uveitis. In this study, we used an experimental autoimmune uveitis (EAU), a representative model for human AU, to investigate the effect of apremilast on regulating anti-inflammatory mediators. Our study demonstrated that apremilast treatment resulted in a decrease in vascular leakage, macular edema, and inflammatory cell infiltration in the retina, corresponding to decreased clinical and pathological scores. Specifically, apremilast decreased the proportion and population of Th17 cells and increased the proportion and population of T regulatory (Treg) cells. Mechanistically, apremilast may regulate Th17 and Treg cells by inhibiting the phosphorylation of the phosphoinositide 3-kinase (PI3K)/protein kinase B(AKT)/Forkhead box O1 (FoxO1) signaling pathway. These findings suggested that apremilast alleviated EAU by regulating Th17 and Treg through the PI3K/AKT/FoxO1 pathway.

The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases

“…Furthermore, appropriate PI3K functioning is essential for the maintenance of Treg cell generation and function, whereas excessive PI3K activity seems to be detrimental. The effect and mechanism of action of PI3K on the Th17/Treg balance may be multifaceted, including promotion of mTOR activity and glucose uptake, mediated by distinct PI3K isoenzymes ( 64 ). Indeed, the effects of PI3K/Akt signaling exerted on the function and frequency of Treg cell populations and their importance in Th17 cell differentiation remain unknown.…”

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway

“…However, severe unacceptable adverse events, including nausea and vomiting, blocked the clinical application of rolipram (22). Researchers subsequently invented apremilast, a newer third-generation PDE4 inhibitor, by using a recognized functional pharmacophore of earlier PDE4 inhibitors and adding a series of active groups in order to reduce side effects and optimize pharmaceutical effects (23). However, clinical evidence suggests that treatment with repeated dosing of roflumilast may lead to the development of tachyphylaxis or tolerance for roflumilast through up-regulation of PDE4B expression (24).…”

Psoriatic Arthritis: Pathogenetic Justification of Current Therapeutic Approaches

“…В последние годы был разработан и предложен к применению ингибитор фосфодиэстеразы (ФДЭ-4) апремиласт, который относят к группе таргетных синтетических БПВП. Апремиласт имеет благоприятный профиль безопасности, зарегистрирован в США и Европе для лечения активного ПсА или псориаза у пациентов, которые не проходили лечение с использованием БПВП или ГИБП в качестве первой линии терапии [38].…”