Astrocytes respond to inflammatory stimuli by adopting a reactive state characterized by morphological, molecular, and functional changes that affect tissue repair and disease progression. A key feature of this transformation is the metabolic shift that supports inflammatory signaling and cytokine production. Retinoic acid (RA) modulates immune responses in the peripheral system; however, its role in astrocyte reactivity remains poorly understood. In this study, we investigated alterations in RA metabolism using an in vitro model of reactive astrocytes derived from human pluripotent stem cells. Reactivity was induced by treatment with tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), collectively referred to as TIC, and characterized using comprehensive morphological, molecular and functional analyses. We found that the induced reactive astrocytes exhibited a marked downregulation of key biosynthetic enzymes in RA metabolism, leading to a net decrease in intracellular RA levels. Exogenous RA supplementation attenuated TIC-induced expression of pro- and anti-inflammatory mediators, including IL-6, IL-8, nitric oxide, IL-10, and TGFβ. Mechanistically, RA suppressed these inflammatory responses by inhibiting NF-κB activation, likely through upstream attenuation of ERK and p38 MAPK pathways via upregulation of MAPK phosphatase 1 (MKP-1). In neuron and TIC-treated astrocyte co-cultures, RA treatment reduced the density of cleaved caspase 3-positive apoptotic-like neurons, an effect accompanied by decreased nitric oxide levels. These observations coincided with the restoration of mitochondrial integrity and mitophagy. Taken together, these findings identify RA metabolism as a key regulatory node in astrocyte reactivity and suggest a potential therapeutic role for RA in neuroinflammatory conditions. • Reactive astrocytes induced by the inflammatory mediator cocktail suppress RA biosynthesis. • Exogenous RA lowers astrocyte inflammation by blocking the MAPK-NF-κB signaling pathway. • RA supplementation also attenuates inflammation, restores mitochondrial function, and promotes neuronal survival.
Yoo et al. (Sun,) studied this question.