GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia

Parajuli, Bijay; Sonobe, Yoshifumi; Koyama, Jun; Doi, Yukiko; Noda, Mariko; Takeuchi, Hideyuki; Mizuno, Tetsuya; Suzumura, Akio

doi:10.1186/1742-2094-9-268

Cited by 129 publications

(104 citation statements)

References 56 publications

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“…In this study, we showed that high potential of SKG T cells to produce GM-CSF produced a different outcome between zymosan-treated SKG and BALB/c. GM-CSF was reported to upregulate TLR2, TLR4, and CD14 expression (41)(42)(43) and boost IL-6 and IL-1b production from macrophages (41,44,45). Although serum concentration of GM-CSF in zymosan-treated SKG mice was very low and could not be detected by ELISA, we showed that GM-CSF could enhance the production of IL-6 and IL-1b by macrophages even at a low concentration (Fig.…”

Section: Discussionmentioning

confidence: 72%

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Shiomi

Usui

Ishikawa

et al. 2014

The Journal of Immunology

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Interstitial lung disease (ILD) is a common complication and sometimes a prognostic factor of connective tissue diseases (CTDs) in humans. However, suitable animal model of severe CTD-associated ILD (CTD-ILD) has been limited. In this study, we showed that zymosan-treated SKG mice developed not only arthritis but also chronic–progressive ILD with high mortality over several months. The pathological and clinical features of ILD in zymosan-treated SKG mice were similar to that of human severe CTD-ILD. ILD in this mouse was characterized by massive infiltration of Th17 cells, GM-CSF–producing CD4+ T cells, and CD11b+ Gr1+ neutrophils with fibrosis. Naive SKG T cells were skewed to differentiate into GM-CSF–producing cells, and GM-CSF secreted by T cells enhanced IL-6 and IL-1β production by macrophages, which in turn enhanced differentiation of IL-17A– and/or GM-CSF–producing T cells and infiltration of neutrophils into lung. Neutralization of GM-CSF completely blocked the development of this ILD, and the blocking of IL-6 signaling resulted in partial prevention of it, whereas neutralization of IL-17A did not. In contrast, the progression of arthritis was inhibited by the neutralization of GM-CSF and slightly by the neutralization of IL-17A, but not by the blocking of IL-6 signaling. These data suggested zymosan-treated SKG mice could be a useful mouse model of severe CTD-ILD, and GM-CSF, rather than IL-17A or IL-6, contributed to the development of ILD in zymosan-treated SKG mice, indicating that neutralization of GM-CSF would be a useful therapeutic strategy for severe CTD-ILD.

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Section: Discussionmentioning

confidence: 72%

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Shiomi

Usui

Ishikawa

et al. 2014

The Journal of Immunology

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“…Several lines of evidence have confirmed that systemic administration of LPS increases the production of inflammatory mediators including iNOS, COX2, and different cytokines such as TNF-α, IL-1β, and IL-6, which induce a number of neurobiological effects (PalssonMcDermott and O'Neill 2004;Parajuli et al 2012). Neuroinflammation has been shown to induce neurodegeneration in different forms of brain disorders such as sepsis, Alzheimer's disease, Parkinson's disease, and multiple sclerosis (Gao and Hong 2008;Lull and Block 2010).…”

Section: Discussionmentioning

confidence: 95%

Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

Badshah

Ali

Rehman

et al. 2015

J Neuroimmune Pharmacol

101

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Recent studies have demonstrated a close interaction between neuroinflammatory responses, increased production of inflammatory mediators, and neurodegeneration. Pathological findings in neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease have shown common signs of neuroinflammation and neurodegeneration. Lupeol, a natural pentacyclic triterpene, has revealed a number of pharmacological properties including an anti-inflammatory activity. This study aimed to evaluate the effect of lupeol against lipopolysaccharide (LPS)-induced neuroinflammation in the cortex and hippocampus of adult mice. Our results showed that systemic administration of LPS induced glial cell production of proinflammatory cytokines, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and interleukin (IL)-1β, while co-treatment with lupeol significantly inhibited the LPS-induced activation of microglia and astrocytes, and decreased the LPS-induced generation of TNF-α, iNOS, and IL-1β. The intracellular mechanism involved in the LPS-induced activation of inflammatory responses includes phosphorylation of P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), which was significantly inhibited by lupeol. We further elucidated that lupeol inhibited the LPS-induced activation of the mitochondrial apoptotic pathway and reversed the LPS-induced expression of apoptotic markers such as Bax, cytochrome C, caspase-9, and caspase-3. Taken together; our results suggest that lupeol inhibits LPS-induced microglial neuroinflammation via the P38-MAPK and JNK pathways and has therapeutic potential to treat various neuroinflammatory disorders.

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“…Our results showed that this concentration of AFB 1 could induce an inflammatory response on the human microglial cells, but it cannot convert them to the M2 phenotype of microglial cells. As the microglial cells act like a sensor of inflammation in the brain [32], it could be expected that the observed overexpression of TLRs is the reason for GM-CSF secretion in the AFB 1 -exposed microglia as a signal of danger for other resting microglial cells [33]; the increased GM-CSF can also lead to increased recruitment of inflammatory cells into the brain [34]. As such, GM-CSF could simply induce microglial cell proliferation [35], further boosting the proinflammatory/toxic/dysregulatory microenvironment in the brain.…”

Section: Discussionmentioning

confidence: 99%

Human Microglial Cells Undergo Proapoptotic Induction and Inflammatory Activation upon in vitro Exposure to a Naturally Occurring Level of Aflatoxin B<sub>1</sub>

Mehrzad

Hosseinkhani

Malvandi

2018

Neuroimmunomodulation

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Objective: Knowledge regarding interactions of AFB₁ with the human nervous system and how a naturally occurring level of AFB₁ could potentially induce neuroimmune dysregulation is very limited. To assess the cellular effects of AFB₁ on the human brain, we used the human microglia cell line CHME5 as a model to pinpoint its potential in vivo translation. Methods: We used the CHME5 cell line culture system, multiplex qPCR, (chemi)bioluminescence, Luminex ELISA, and flow cytometry assays to evaluate the toxic effects of a naturally occurring level of AFB₁ on human microglia. Results: A low concentration of AFB₁ upregulates the mRNA expression of many proinflammatory molecules, such as TLRs, MyD88, NFκB, and CxCr4, induces intracellular ATP depletion, and increases caspase-3/7 activity at different time points following exposure to the toxin. Furthermore, AFB₁-exposed microglia secreted significantly higher levels of IFN-γ and GM-CSF after treatment. We also observed a slight increase in the percentage of apoptotic microglia (annexin V⁺/PI⁻) at 48 h posttreatment. Conclusion: Our work confirmed that the environmentally relevant level of AFB₁ could cause an inflammatory reaction in human microglial cells that is potentially harmful or toxic to the homeostasis of the human central nervous system and might increase susceptibility to neurodegenerative diseases.

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GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia

Cited by 129 publications

References 56 publications

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

Human Microglial Cells Undergo Proapoptotic Induction and Inflammatory Activation upon in vitro Exposure to a Naturally Occurring Level of Aflatoxin B<sub>1</sub>

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