Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the <scp>LKB</scp>1–<scp>AMPK</scp> signaling pathway

Ji, Juan; Xue, Tengfei; X, Guo; Yang, Jin; Guo, Ruo-Bing; Wang, Juan; Jian, Huang; Zhao, Xiaojie; Sun, Xiu‐Lan

doi:10.1111/acel.12774

Cited by 177 publications

(124 citation statements)

References 42 publications

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“…To our surprise, rosiglitazone also inhibited proinflammatory microglial polarization, during which the expression of CD206 and Arg-1 is increased. 32 In addition, we observed the loss of neurons in temporal lobe and hippocampal tissues after SE, consistent with the previous study. 48 After rosiglitazone administration, the number of NeuN+ cells was increased 3 days after SE, especially in CA3 hippocampi.…”

Section: Discussionsupporting

confidence: 92%

“…Our study revealed that the PPARγ agonist rosiglitazone can suppress the activation of microglia by flow cytometry and immunofluorescence staining for Iba‐1. To our surprise, rosiglitazone also inhibited proinflammatory microglial polarization, during which the expression of CD206 and Arg‐1 is increased . In addition, we observed the loss of neurons in temporal lobe and hippocampal tissues after SE, consistent with the previous study .…”

Section: Discussionsupporting

confidence: 91%

“…Scale bar = 50 μm There is growing evidence that the PPARγ agonist rosiglitazone prevents microglial activation, promotes microglial antiinflammatory polarization, and suppresses inflammatory cytokines in inflammation-related diseases, such as MS, EAE, and Parkinson's disease. 32 However, the protective effect of rosiglitazone after SE needs to be clarified. Our study revealed that the PPARγ agonist rosiglitazone can suppress the activation of microglia by flow cytometry and immunofluorescence staining for Iba-1.…”

Section: Discussionmentioning

confidence: 99%

“…Growing evidence has shown that the PPAR γ agonist rosiglitazone inhibits lipopolysaccharide (LPS)-induced microglial activation and promotes LPS-stimulated alterations in polarization from the deleterious M1 phenotype to the neuroprotective M2 phenotype in principal microglia. 32 The activation of PPAR γ by pioglitazone and troglitazone reduces infarct volume by refining neurological function after middle cerebral artery occlusion in rats. 33,34 It has also been found that the PPAR γ agonist rosiglitazone imparts antidepressant-and anxiolytic-like effects.…”

Section: Introductionmentioning

confidence: 99%

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Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

et al. 2019

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Aims Activated microglia have been found in the forebrains and hippocampi of temporal lobe epilepsy (TLE) patients and status epileptic (SE) animal models. The peroxisome proliferator‐activated receptor γ (PPAR γ) agonist rosiglitazone has been shown to prevent microglial activation. However, its role in pilocarpine‐induced status epilepticus remains unknown. We aimed to examine the effect of the PPAR γ agonist rosiglitazone in protecting against pilocarpine‐induced status epileptic resulting from over‐activation and to explore phenotypic changes in microglia as the underlying mechanism. Methods Male C57BL/6 mice were assigned to three groups: the control group, pilocarpine‐induced (SE) group, and rosiglitazone‐treated (SE+Rosi) group. Status epileptic mice were administered 300 mg/kg pilocarpine via intraperitoneal injection. SE+Rosi mice were administered rosiglitazone (0.1 mg/kg, i.p.) after SE. Flow cytometry, immunofluorescence staining, and quantitative real‐time PCR were used to examine the activation of and phenotypic changes in microglia in the brain and to evaluate neuroinflammation. Results We found that the expression of proinflammatory CD86 and iNOS was increased and that the expression of antiinflammatory CD206 and Arg‐1 was decreased in the brains of pilocarpine‐induced SE mice compared to control mice. The mRNA levels of proinflammatory and antiinflammatory cytokines were not significantly changed in the brain. Rosiglitazone treatment significantly inhibited the proinflammatory polarization of microglia and rescued neuron loss in the temporal lobe and hippocampi of the brain after SE. Conclusion Rosiglitazone reverses microglial polarization in the brains of SE mice and also affords neuroprotection against pilocarpine‐induced status epilepticus without inducing significant changes in brain inflammation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

et al. 2019

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“…Norbixin by suppressing A2E-induced PPAR-a transactivation may thus release A2E inhibitory effect through PPAR-a resulting in increased CCL2 production. However, antagonizing PPARg also reduces CCL-2 expression during microglia differentiation in vitro (45). Altogether, these conflicting observations suggest that, upon A2E treatment, CCL2 overexpression may result from a subtle equilibrium between RARs, PPAR-a and -g transactivation levels.…”

Section: Discussionmentioning

confidence: 96%

A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cellsin vitro

Fontaine

Fournié

Monteiro

et al. 2020

Preprint

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N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing apoptosis, angiogenesis and inflammation. It has been proposed that A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-a. Here we show that A2E binds and transactivates not only RARs, but also peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs). Norbixin, which protects retinal pigment epithelium (RPE) cells against apoptosis induced by combined blue light illumination and A2E exposure, is also a ligand of these nuclear receptors (NRs) but does not induce their transactivation. Norbixin inhibits RXRs andPPARs but enhances RARs transactivation induced by A2E. Norbixin also inhibits PPAR-g transactivation induced by its high affinity ligand troglitazone. activator protein 1 (AP-1) transactivation, and the mRNA expression of the inflammatory interleukins (IL) 6 and 8 and of vascular endothelial growth factor (VEGF) that are enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression but has neither effect on extracellular signal-regulated kinase (ERK) phosphorylation, nor on IL-18 mRNA Norbixin modulates NRs activation by A2E in RPE cells 2 expression in response to A2E. Altogether, we show for the first time that A2E deleterious biological effects appear to be mediated through RARs, PPARs and RXRs. Moreover, we report that the modulation of these NRs by norbixin may open new avenues for the treatment of AMD. Photoprotection of RPE cells by norbixin correlates with maintained levels of the antiapoptotic B-cell lymphoma 2 (Bcl2) protein. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-kB and

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Jiaohong pills attenuate neuroinflammation and amyloid‐β protein‐induced cognitive deficits by modulating the mitogen‐activated protein kinase/nuclear factor kappa‐B pathway

Zhang,

Cai,

Dong

et al. 2024

Anim Models and Exp Med

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BackgroundJiaohong pills (JHP) consist of Pericarpium Zanthoxyli (PZ) and Radix Rehmanniae, two herbs that have been extensively investigated over many years due to their potential protective effects against cognitive decline and memory impairment. However, the precise mechanisms underlying the beneficial effects remain elusive. Here, research studies were conducted to investigate and validate the therapeutic effects of JHP on Alzheimer's disease.MethodsBV‐2 cell inflammation was induced by lipopolysaccharide. AD mice were administered amyloid‐β (Aβ). Behavioral experiments were used to evaluate learning and memory ability. The levels of nitric oxide (NO), tumor necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), and interleukin‐10 (IL‐10) were detected using enzyme‐linked immunosorbent assay (ELISA). The protein expressions of inducible nitric oxide synthase (iNOS) and the phosphorylation level of mitogen‐activated protein kinase (MAPK) and nuclear factor kappa‐B (NF‐κB) were detected using Western blot. Nissl staining was used to detect neuronal degeneration.ResultsThe results demonstrated that an alcoholic extract of PZ significantly decreased the levels of NO, IL‐1β, TNF‐α, and iNOS; increased the expression level of IL‐10; and significantly decreased the phosphorylation levels of MAPK and NF‐κB. These inhibitory effects were further confirmed in the AD mouse model. Meanwhile, JHP improved learning and memory function in AD mice, reduced neuronal damage, and enriched the Nissl bodies in the hippocampus. Moreover, IL‐1β and TNF‐α in the cortex were significantly downregulated after JHP administration, whereas IL‐10 showed increased expression.ConclusionsIt was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF‐κB signaling pathway.

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Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

Cited by 177 publications

References 42 publications

Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cellsin vitro

Jiaohong pills attenuate neuroinflammation and amyloid‐β protein‐induced cognitive deficits by modulating the mitogen‐activated protein kinase/nuclear factor kappa‐B pathway

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