ArticleAutophagy2019
TLR4 (toll-like receptor 4) activation suppresses autophagy through inhibition of FOXO3 and impairs phagocytic capacity of microglia.
Article in Autophagy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 138 papers, 2 of them syntheses that pooled it.
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Who cites it
138 citing papers in PubMed, 2 syntheses or guidelines pooled it, 254 citations in OpenAlex.
- The Key Drivers of Brain Injury by Systemic Inflammatory Responses after Sepsis: Microglia and Neuroinflammation.Molecular neurobiology · 2023Pooled it
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- ApoE impairs microglial efferocytosis by targeting Gas6/MerTK in a mouse model of acute seizure.Acta pharmacologica Sinica · 2026Article
- RBM15 promotes hyperglycemia-induced retinal endothelial cell injury by regulating FOXO3 stability via m6A modification.Molecular and cellular biochemistry · 2026Article
- Inflammation increases the penetrance of behavioral impairment in Shank3 haploinsufficiency mice - can it explain the behavioral regression in Autism?Molecular psychiatry · 2026Article
- Myelin dysfunction in autism spectrum disorder: insights into core symptoms and mechanisms of brain development.Molecular psychiatry · 2026Review
- A human telomerase reverse transcriptase-derived peptide GV1001 rescues neurodegeneration in a mouse model of Alzheimer disease.Experimental & molecular medicine · 2026Article
- Arsenic attenuates responsiveness to inflammatory stimuli in the SIM-A9 microglial cell line.Neurotoxicology · 2026Article
- Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs.Nature neuroscience · 2026Article
- DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB.Nature communications · 2026Article
- microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer's disease patients.Acta neuropathologica communications · 2026Article
- TFEB, FOXO3 and TLR4 in resveratrol-induced autophagy in a mucopolysaccharidosis IIIB mouse model.Experimental & molecular medicine · 2026Article
- Role of Microglial Dysfunction in Parkinson's Disease: From Multifactorial Causes to Neurodegeneration.Neuroscience bulletin · 2026Review
- Adolescent exposure to polystyrene nanoplastics induces male reproductive damage via the microbiome-gut-testis axis.Journal of nanobiotechnology · 2026Article
- Hypothalamic neuroimmune remodeling as an immunometabolic bridge between childhood obesity and earlier pubertal onset.Frontiers in immunology · 2026Review
- TLR4 mediates post-traumatic depression via kynurenine pathway activation in a murine traumatic brain injury model.Frontiers in pharmacology · 2026Article
- Unraveling the anti-neuroinflammatory mechanisms of Cervus cucumis polypeptide injection in Alzheimer's disease: insights from network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.Frontiers in aging neuroscience · 2026Article
- TLR9 decreases FOXO3 expression to prevent excessive inflammation in macrophage activation syndrome.iScience · 2025Article
- SIRT2 Inhibition promotes microglia LC3-associated phagocytosis via NRF2/CD36 after the experimental subarachnoid hemorrhage.Journal of neuroinflammation · 2025Article
- Multifaceted role of nitric oxide in vascular dementia.Medical gas research · 2025Review
78 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Macroautophagy/autophagy is a lysosome-dependent catabolic process for the turnover of proteins and organelles in eukaryotes. Autophagy plays an important role in immunity and inflammation, as well as metabolism and cell survival. Diverse immune and inflammatory signals induce autophagy in macrophages through pattern recognition receptors, such as toll-like receptors (TLRs). However, the physiological role of autophagy and its signaling mechanisms in microglia remain poorly understood. Microglia are phagocytic immune cells that are resident in the central nervous system and share many characteristics with macrophages. Here, we show that autophagic flux and expression of autophagy-related (Atg) genes in microglia are significantly suppressed upon TLR4 activation by lipopolysaccharide (LPS), in contrast to their stimulation by LPS in macrophages. Metabolomics analysis of the levels of phosphatidylinositol (PtdIns) and its 3-phosphorylated form, PtdIns3P, in combination with bioinformatics prediction, revealed an LPS-induced reduction in the synthesis of PtdIns and PtdIns3P in microglia but not macrophages. Interestingly, inhibition of PI3K, but not MTOR or MAPK1/3, restored autophagic flux with concomitant dephosphorylation and nuclear translocation of FOXO3. A constitutively active form of FOXO3 also induced autophagy, suggesting FOXO3 as a downstream target of the PI3K pathway for autophagy inhibition. LPS treatment impaired phagocytic capacity of microglia, including MAP1LC3B/LC3-associated phagocytosis (LAP) and amyloid β (Aβ) clearance. PI3K inhibition restored LAP and degradation capacity of microglia against Aβ. These findings suggest a unique mechanism for the regulation of microglial autophagy and point to the PI3K-FOXO3 pathway as a potential therapeutic target to regulate microglial function in brain disorders. Abbreviations: Atg: autophagy-related gene; Aβ: amyloid-β; BafA1: bafilomycin A
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.