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Globular Adiponectin Limits Microglia Pro-Inflammatory Phenotype through an AdipoR1/NF-?B Signaling Pathway.

ABSTRACT: We recently reported that increased levels of Adiponectin (ApN) in the brain led to microglia phenotype and activation state regulation, thus reducing both global brain inflammation and depressive-like behaviors in mice. Apart from this, little is known on ApN molecular effects on microglia, although these cells are crucial in both physiological and pathological processes. Here we fill this gap by studying the effects and targets of ApN toward neuroinflammation. Our findings suggest that ApN deficiency in mice leads to a higher sensitivity of mice to neuroinflammation that is due to enhanced microglia responsiveness to a pro-inflammatory challenge. Moreover, we show that globular ApN (gApN) exerts direct in vivo anti-inflammatory actions on microglia by reducing IL-1?, IL-6, and TNF? synthesis. In vitro, gApN anti-inflammatory properties are confirmed in brain-sorted microglia, primary cultured and microglia cell line (BV2), but are not observed on astrocytes. Our results also show that gApN blocks LPS-induced nitrosative and oxidative stress in microglia. Finally, we demonstrate for the first time that these anti-inflammatory and anti-oxidant actions of gApN on microglia are mediated through an AdipoR1/NF-?B signaling pathway.

SUBMITTER: Nicolas S

PROVIDER: S-EPMC5694456 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Globular Adiponectin Limits Microglia Pro-Inflammatory Phenotype through an AdipoR1/NF-κB Signaling Pathway.

Nicolas Sarah S Cazareth Julie J Zarif Hadi H Guyon Alice A Heurteaux Catherine C Chabry Joëlle J Petit-Paitel Agnès A

Frontiers in cellular neuroscience 20171114

We recently reported that increased levels of Adiponectin (ApN) in the brain led to microglia phenotype and activation state regulation, thus reducing both global brain inflammation and depressive-like behaviors in mice. Apart from this, little is known on ApN molecular effects on microglia, although these cells are crucial in both physiological and pathological processes. Here we fill this gap by studying the effects and targets of ApN toward neuroinflammation. Our findings suggest that ApN def ...[more]

PMID: 29184485

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Project description:BackgroundMicroglia-mediated neuroinflammation is important in Alzheimer's disease (AD) pathogenesis. Extracellular deposition of β-amyloid (Aβ), a major pathological hallmark of AD, can induce microglia activation. Adiponectin (APN), an adipocyte-derived adipokine, exerts anti-inflammatory effects in the periphery and brain. Chronic APN deficiency leads to cognitive impairment and AD-like pathologies in aged mice. Here, we aim to study the role of APN in regulating microglia-mediated neuroinflammation in AD.MethodsInflammatory response of cultured microglia (BV2 cells) to AβO and effects of APN were studied by measuring levels of proinflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin-1β [IL-1β]) in cultured medium before and after exposure to AβO, with and without APN pretreatment. Adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) were targeted by small interference RNA. To study the neuroprotective effect of APN, cultured HT-22 hippocampal cells were treated with conditioned medium of AβO-exposed BV2 cells or were co-cultured with BV2 cells in transwells. The cytotoxicity of HT-22 hippocampal cells was assessed by MTT reduction. We generated APN-deficient AD mice (APN-/-5xFAD) by crossing APN-knockout mice with 5xFAD mice to determine the effects of APN deficiency on microglia-mediated neuroinflammation in AD.ResultsAdipoR1 and AdipoR2 were expressed in BV2 cells and microglia of mice. Pretreatment with APN for 2 h suppressed TNFα and IL-1β release induced by AβO in BV2 cells. Additionally, APN rescued the decrease of AMPK phosphorylation and suppressed nuclear translocation of nuclear factor kappa B (NF-κB) induced by AβO. Compound C, an inhibitor of AMPK, abolished these effects of APN. Knockdown of AdipoR1, but not AdipoR2 in BV2 cells, inhibited the ability of APN to suppress proinflammatory cytokine release induced by AβO. Moreover, pretreatment with APN inhibited the cytotoxicity of HT-22 cells co-cultured with AβO-exposed BV2 cells. Lastly, APN deficiency exacerbated microglia activation in 9-month-old APN-/-5xFAD mice associated with upregulation of TNFα and IL-1β in the cortex and hippocampus.ConclusionsOur findings demonstrate that APN inhibits inflammatory response of microglia to AβO via AdipoR1-AMPK-NF-κB signaling, and APN deficiency aggravates microglia activation and neuroinflammation in AD mice. APN may be a novel therapeutic agent for inhibiting neuroinflammation in AD.

Project description:BackgroundNeuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway.MethodsThe putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells.ResultsCPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells.ConclusionsThese results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation.

Project description:Atrial hypertrophy and fibrosis are essential pathological features of atrial fibrillation. Recently, adiponectin has become a protein of interest due to its beneficial effects on cardiovascular diseases. However, the molecular mechanism of atrial structural remodeling and signaling pathways evoked by adiponectin remain unclear. In the present study, we investigated the cardioprotective effect of globular adiponectin (gAcrp) on angiotensin II-induced atrial hypertrophy and fibrosis in neonatal Sprague-Dawley rat. To further investigate the molecular mechanisms underlying the preventive effect of gAcrp, transfection of cells with siRNA was used to suppress the mRNA expression of adiponectin receptor 1 (AdipoR1) and its downstream adaptor protein APPL1. Non-silencing-Cy-3 labelled siRNA was used to determine transfection efficiency using fluorescence microscopy. The expression of atrial natriuretic peptide and procollagen type1 ?-1, hypertrophy marker and fibrosis one, respectively, was detected by real-time PCR. Furthermore, the expression of adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K) and Akt was detected by western blotting. In addition, nuclear p65 translocation activity was analyzed by EMSA supershift assay. Our results showed that AdipoR1 and the adaptor protein APPL1 mediated the protective effects of gAcrp. In addition, the function of adiponectin and phosphorylation of AMPK were prominently diminished by inhibition of PI3K. Furthermore, nuclear factor-?B (NF-?B) transcription was diminished by the specific inhibition of AMPK. Taken together, AMPK pivotally interacts with NF-?B and PI3K, mediating the cardioprotective effect of adiponectin, and may serve as a therapeutic target for preventing atrial hypertrophy and fibrosis. Our present study suggests that gAcrp could ameliorate AngII-induced cardiac hypertrophy and fibrosis in rat atrial cells, which is mediated by the activation of AMPK signaling pathways. APPL1 and AdipoR1 are the key factors involved in the downstream of gAcrp approach.

Project description:ContextCurrent epidemiological evidence suggests an association between obesity, hyperinsulinemia, and colorectal cancer risk. Adiponectin is a hormone secreted by the adipose tissue, and serum levels are inversely correlated with obesity and hyperinsulinemia. While there is evidence of an association between circulating adiponectin levels and colorectal cancer risk, no association between genes of the adiponectin pathway and colorectal cancer have been reported to date.ObjectiveTo determine the association of 10 haplotype-tagging single-nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with colorectal cancer risk.Design, setting, and patientsTwo case-control studies including patients with a diagnosis of colorectal cancer and controls were recruited between 2000 and 2007. Case-control study 1 included a total of 441 patients with a diagnosis of colorectal cancer and 658 controls; both groups were of Ashkenazi Jewish ancestry and from New York, New York. Case-control study 2 included 199 patients with a diagnosis of colorectal cancer and 199 controls from Chicago, Illinois, matched 1:1 for sex, age, and ethnicity.Main outcome measuresADIPOQ and ADIPOR1 SNP frequency among cases and controls.ResultsIn study 1, after adjustment for age, sex, and SNPs from the same gene, 3 ADIPOQ SNPs and 1 ADIPOR1 SNP were associated with colorectal cancer risk: rs266729 (adjusted odds ratio [AOR], 0.72; 95% confidence interval [CI], 0.55-0.95) and rs822396 (AOR, 0.37; 95% CI, 0.14-1.00) were associated with decreased risk whereas rs822395 (AOR, 1.76; 95% CI, 1.09-2.84) and rs1342387 (AOR, 1.79; 95% CI, 1.18-2.72) were associated with increased risk. In study 2, after adjustment for age, sex, race, and SNPs from the same gene, the ADIPOQ SNP rs266729 was associated with a decreased colorectal cancer risk of similar magnitude as in study 1 (AOR, 0.52; 95% CI, 0.34-0.78). Combined analysis of both studies shows an association of rs266729 with decreased colorectal cancer risk (AOR, 0.73; 95% CI, 0.53-0.99).ConclusionThe SNP rs266729, which tags the 5' flanking region of the ADIPOQ gene, is associated with decreased colorectal cancer risk.

Project description:The aim of the present study was to examine whether adiponectin could inhibit cardiomyocyte senescence induced by D‑galactose (D‑gal), and whether it functioned via the adiponectin receptor 1 (AdipoR1)/adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) signaling pathway. For this purpose, the expression levels of adiponectin, AdipoR1 and APPL1 in mouse plasma and myocardial tissues were detected via reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. An adiponectin‑overexpression plasmid was transfected into D‑gal‑treated H9c2 cells prior to the detection of AdipoR1 and APPL1 expression by RT‑qPCR. Senescence‑associated β‑galactose staining was then performed to observe cellular senescence following the transfection of small interfering RNAs (si) targeting AdipoR1 and APPL1 into D‑gal‑treated H9c2 cells overexpressing adiponectin. Commercial kits were used to detect reactive oxygen species (ROS) production and malondialdehyde (MDA) content in the different groups. The expression levels of heme oxygenase (HO)‑1 and high mobility group box 1 (HMGB1) were examined by western blot analysis. The results revealed that the expression levels of adiponectin, AdipoR1 and APPL1 were downregulated in aged mouse plasma, myocardial tissues and D‑gal‑treated cardiomyocytes. It was also observed that AdipoR1 and APPL1 expression levels were significantly upregulated following the overexpression of adiponectin into D‑gal‑treated cardiomyocytes. Moreover, adiponectin overexpression reduced cellular senescence induced by D‑gal and the expression of p16 and p21; these effects were reversed following transfection with si‑AdipoR1 and si‑APPL1. Adiponectin also downregulated the levels of ROS and MDA in D‑gal‑treated H9c2 cells via AdipoR1/APPL1. Additionally, the release of HO‑11/HMGB1 was affected by adiponectin via AdipoR1/APPL1, and adiponectin/AdipoR1/APPL1 suppressed ROS production via HO‑1/HMGB1. On the whole, the present study demonstrated that adiponectin played an inhibitory role in cardiomyocyte senescence via the AdioR1/APPL1 signaling pathway and inhibited the levels of oxidative stress in senescent cardiomyocytes via the HO‑1/HMGB1 signaling pathway.

Dataset Information

Globular Adiponectin Limits Microglia Pro-Inflammatory Phenotype through an AdipoR1/NF-?B Signaling Pathway.

Publications

Globular Adiponectin Limits Microglia Pro-Inflammatory Phenotype through an AdipoR1/NF-κB Signaling Pathway.

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