Cargando…

TMAO Promotes NLRP3 Inflammasome Activation of Microglia Aggravating Neurological Injury in Ischemic Stroke Through FTO/IGF2BP2

OBJECTIVE: Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. MATERIALS AND METHODS: Mice were fed with 0.12% TMAO for 16 weeks. Then, mice were made into MCAO/R models. Neurological score, infarct vol...

Descripción completa

Detalles Bibliográficos
Autores principales: Ge, Pengxin, Duan, Huijie, Tao, Chunrong, Niu, Sensen, Hu, Yiran, Duan, Rui, Shen, Aizong, Sun, Yancai, Sun, Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473438/
https://www.ncbi.nlm.nih.gov/pubmed/37663757
http://dx.doi.org/10.2147/JIR.S399480
Descripción
Sumario:OBJECTIVE: Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. MATERIALS AND METHODS: Mice were fed with 0.12% TMAO for 16 weeks. Then, mice were made into MCAO/R models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in ischemic stroke, microglia of MCAO/R mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia. RESULTS: TMAO promoted the release of inflammatory cytokines in the brain of MCAO/R mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating ischemic stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3. TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2. CONCLUSION: Our results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in ischemic stroke through FTO/IGF2BP2. These findings explained the molecular mechanism of TMAO aggravating ischemic stroke in detail and provided molecular mechanism for clinical treatment.