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Paraspeckles translate microbial insult-induced inflammation into neurovascular remodeling by enhancing CYR61-FGF2
Jia-Qi Pan1, Kai-Tong Yang1, Jing-Qian Zhang1
1Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Jiangnan University-Xinshijie Eye Hospital Joint Ophthalmic Research Center, Wuxi, Jiangsu, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
Background:
Systemic inflammation triggered by microbial insults can disrupt endothelial homeostasis, impair blood-brain and blood-retinal barriers, leading to neurovascular remodeling in the central nervous system (CNS). Subnuclear condensates, paraspeckles, play a substantial role in stress-induced gene regulation, yet their contribution to the inflammatory relay from microbial insults to neurovascular remodeling remains unelucidated.
Results:
Our comparative transcriptomic analysis followed by experimental validation identified a cross-species NEAT1_2/CYR61/FGF2 signature in the CNS positively associated with neurovascular remodeling across human disease cohorts and multiple mouse models. Notably, systemic inflammation triggered by microbial insults, including sepsis or gut dysbiosis, enhanced NEAT1_2 expression in the brain and retina with neurovascular remodeling. Microbial insults induced hyper-assembly of paraspeckles and the expression of CYR61 and FGF2 in vascular endothelial cells. Paraspeckle assembly and its required NEAT1_2 Domain C, rather than NEAT1_2 expression levels, play a pivotal role in endothelial homeostasis control and neurovascular remodeling by sequestering the RNA-binding protein RBM14 within paraspeckles, thereby relieving its transcriptional repression of the CYR61 promoter. Moreover, secreted CYR61 enhanced FGF2-mediated endothelial remodeling signals in a paracrine manner. Disrupting paraspeckle assembly by targeting Domain C intercepts neurovascular remodeling, restoring endothelial homeostasis in vivo.
Conclusions:
Our results demonstrate an essential and conserved role for paraspeckles in the inflammatory relay from microbial insults to neurovascular remodeling by sequestering RBM14 to enhance CYR61-FGF2 signaling. Furthermore, our study underscores paraspeckle assembly as a promising therapeutic target for neurovascular remodeling and related diseases.
