ArticleBrain, behavior, and immunity2016
Neurons and astroglia govern microglial endotoxin tolerance through macrophage colony-stimulating factor receptor-mediated ERK1/2 signals.
Article in Brain, behavior, and immunity, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 42 citations in OpenAlex.
- Adolescent M-CSF Administration Provides Durable Protection Against Trauma-Induced PTSD-Like Phenotypes in Male Mice Through Microglia-Dependent Mechanisms.Neurochemical research · 2026Article
- Interactions between Innate Immune Memory and the Central Nervous System.Neuroimmunomodulation · 2026Review
- Innate Immune Tolerance Regulates Microglia Response to Aβ Oligomers.Journal of neurochemistry · 2026Article
- Gut-derived small extracellular vesicles support trained innate immune tolerance in murine microglial cells.Frontiers in immunology · 2026Article
- Induction of endogenous IL-10 promotes resolution and tolerance of nitric oxide in microglia.Brain, behavior, & immunity - health · 2025Article
- Macrophage colony-stimulating factor and its role in the tumor microenvironment: novel therapeutic avenues and mechanistic insights.Frontiers in oncology · 2024Review
- Gut microbiota and tumor-associated macrophages: potential in tumor diagnosis and treatment.Gut microbes · 2023Review
- Tolerized Microglia Protect Neurons Against Endotoxin-Induced TNF-α Production via an LBP-Dependent Intracellular p38 MAPK Signaling Pathway.Inflammation · 2023Article
- Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice.Brain sciences · 2023Article
- Training vs. Tolerance: The Yin/Yang of the Innate Immune System.Biomedicines · 2023Review
- Oral route lipopolysaccharide as a potential dementia preventive agent inducing neuroprotective microglia.Frontiers in immunology · 2023Review
- Neuron-Microglia Contacts Govern the PGEBiomedicines · 2022Article
- Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice.Journal of neuroinflammation · 2022Article
- Low-dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia.Neural regeneration research · 2021Review
- Prevention of Diabetes-Associated Cognitive Dysfunction Through Oral Administration of Lipopolysaccharide Derived FromFrontiers in immunology · 2021Article
- A unique hybrid characteristic having both pro- and anti-inflammatory phenotype transformed by repetitive low-dose lipopolysaccharide in C8-B4 microglia.Scientific reports · 2020Article
- The vasculature in sepsis: delivering poison or remedy to the brain?The Journal of clinical investigation · 2019Article
- Microglial cell loss after ischemic stroke favors brain neutrophil accumulation.Acta neuropathologica · 2019Article
- S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- Chronic pain and impaired glial glutamate transporter function in lupus-prone mice are ameliorated by blocking macrophage colony-stimulating factor-1 receptors.Journal of neurochemistry · 2017Article
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Endotoxin tolerance (ET) is a reduced responsiveness of innate immune cells like macrophages/monocytes to an endotoxin challenge following a previous encounter with the endotoxin. Although ET in peripheral systems has been well studied, little is known about ET in the brain. The present study showed that brain immune cells, microglia, being different from peripheral macrophages, displayed non-cell autonomous mechanisms in ET formation. Specifically, neurons and astroglia were indispensable for microglial ET. Macrophage colony-stimulating factor (M-CSF) secreted from these non-immune cells was essential for governing microglial ET. Neutralization of M-CSF deprived the neuron-glia conditioned medium of its ability to enable microglia to form ET when microglia encountered two lipopolysaccharide (LPS) treatments. Recombinant M-CSF protein rendered enriched microglia refractory to the second LPS challenge leading to microglial ET. Activation of microglial M-CSF receptor (M-CSFR; also known as CSF1R) and the downstream ERK1/2 signals was responsible for M-CSF-mediated microglial ET. Endotoxin-tolerant microglia in neuron-glia cultures displayed M2-like polarized phenotypes, as shown by upregulation of M2 marker Arg-1, elevated production of anti-inflammatory cytokine interleukin 10, and decreased secretion of pro-inflammatory mediators (tumor necrosis factor α, nitric oxide, prostaglandin E2 and interleukin 1β). Endotoxin-tolerant microglia protected neurons against LPS-elicited inflammatory insults, as shown by reduced neuronal damages in LPS pre-treatment group compared with the group without LPS pre-treatment. Moreover, while neurons and astroglia became injured during chronic neuroinflammation, microglia failed to form ET. Thus, this study identified a distinct non-cell autonomous mechanism of microglial ET. Interactions of M-CSF secreted by neurons and astroglia with microglial M-CSFR programed microglial ET. Loss of microglial ET could be an important pathogenetic mechanism of inflammation-associated neuronal damages.
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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.