Astrocyte FGF7/FGFR2 autocrine signaling mediates neuroinflammation and promotes MPTP-induced degeneration of dopaminergic neurons

作者：Xin Sun, Yueping Wang, Yajie Zhang, Ruixue Han, Min Wang, Jing Zhang, Ting Sun, Yang Liu, Gang Hu, Lei Cao, Ming Lu · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.07.012 · 被引用次数：4 · 研究领域：Fibroblast Growth Factor Research、Epigenetics and DNA Methylation、Adenosine and Purinergic Signaling

Reactive astrocytes, which exhibit a correlation with the degeneration of dopaminergic neurons, are present in a considerable number during the progression of Parkinson’s disease (PD). However, the underlying factors shaping astrocyte reactivity and neuroinflammation in PD remain inadequately elucidated. Here, we demonstrate that fibroblast growth factor 7 (FGF7)/FGF receptor 2 (FGFR2) autocrine signaling intensifies astrocyte reactivity and inflammation. Genetic deletion of Arrb2 , β -Arrestin2 encoding gene, led to escalated astrocyte reactivity in MPTP-treated mice, which was further substantiated in astrocyte-specific Arrb2 knockdown mice. RNA sequencing profiling of Arrb2 knockout astrocytes identified Fgf7 as a critical effector of astrocyte reactivity. Subsequently, conditional knockdown of Fgf7 and its receptor Fgfr2 in astrocytes elicited advantageous effects for MPTP-treated mice by restraining the inflammatory phenotypic transition of reactive astrocytes. Furthermore, deletion of astrocytic Fgf7 mitigated MPTP-induced pathology in Arrb2 knockout mice. Mechanistically, STAT1 was distinguished as the transcription factor suppressing Fgf7 expression, while β -Arrestin2 counteracted the proteasomal degradation of STAT1 by binding to RNF220, an E3 ubiquitin ligase for STAT1. More importantly, selectively engaging dopamine D2 receptor (Drd2)/ β -Arrestin2-biased signaling using the agonist UNC9995 exhibited therapeutic potential in MPTP-treated mice via moderation of ast...