Evidence of impairment of normal inflammatory reaction by a high-fat diet

Laflamme, Christian; Bertheau-Mailhot, Geneviève; Giambelluca, Miriam S.; Cloutier, Nathalie; Boilard, Éric; Pouliot, Marc

doi:10.1038/gene.2014.8

Cited by 3 publications

(14 citation statements)

References 48 publications

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“…1B) . In this model, ~90% of all total leukocytes enumerated in LPS‐injected air pouches, are granulocytes (28). Differential leukocyte counts indicated that LiCl decreased the number of granulocytes migrating into the LPS‐injected pouches by ~40% (Fig.…”

Section: Resultsmentioning

confidence: 99%

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TNF‐α expression in neutrophils and its regulation by glycogen synthase kinase‐3: A potentiating role for lithium

et al. 2014

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Glycogen synthase kinase 3 (GSK-3) is associated with several cellular systems, including immune response. Lithium, a widely used pharmacological treatment for bipolar disorder, is a GSK-3 inhibitor. GSK-3α is the predominant isoform in human neutrophils. In this study, we examined the effect of GSK-3 inhibition on the production of TNF-α by neutrophils. In the murine air pouch model of inflammation, lithium chloride (LiCl) amplified TNF-α release. In lipopolysaccharide-stimulated human neutrophils, GSK-3 inhibitors mimicked the effect of LiCl, each potentiating TNF-α release after 4 h, in a concentration-dependent fashion, by up to a 3-fold increase (ED50 of 1 mM for lithium). LiCl had no significant effect on cell viability. A positive association was revealed between GSK-3 inhibition and prolonged activation of the p38/MNK1/eIF4E pathway of mRNA translation. Using lysine and arginine labeled with stable heavy isotopes followed by quantitative mass spectrometry, we determined that GSK-3 inhibition markedly increases (by more than 3-fold) de novo TNF-α protein synthesis. Our findings shed light on a novel mechanism of control of TNF-α expression in neutrophils with GSK-3 regulating mRNA translation and raise the possibility that lithium could be having a hitherto unforeseen effect on inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

“…Viability was >85%, as determined by trypan blue dye exclusion. Nearly all (>95%) of the cells migrating into the LPS‐injected pouch were granulocytes (28).…”

Section: Methodsmentioning

confidence: 99%

TNF‐α expression in neutrophils and its regulation by glycogen synthase kinase‐3: A potentiating role for lithium

et al. 2014

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“…The mRNA transcript level was monitored in mouse dermal fibroblasts using real-time PCR as described by Laflamme et al (2014) . Briefly, reverse transcription was performed using 1 µg of total RNA with a Transcriptor First Strand cDNA Synthesis Kit (Roche Applied Science, Laval, QC, Canada) following the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Complementary DNA amplifications were performed in a Rotor-Gene Q operated with Q-series software version 2.0.2 (Qiagen Inc., Mississauga, ON, Canada) using 35 cycles of 95 °C for 17 s, 58 °C for 25 s and 72 °C for 25 s. Each reaction mixture contained 40 ng of cDNA, 2 µL of 10× Buffer, 100 µM of dNTPs, 0.1 unit of Taq DNA polymerase (Roche Applied Science) and SYBR Green I (Life Technologies Inc., Burlington, ON, Canada) diluted 1:30,000. For each murine gene of interest, specific primers were designed following certain specifications as described by Laflamme et al (2014) . For the LAMP1 gene, the following primers were used: 5′-ACTGGTAACAACGGAACCTG-3′ (forward) and 5′-ACACATTGGGGTTAGGAACA-3′ (reverse).…”

Section: Methodsmentioning

confidence: 99%

Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models

Parks

Charest‐Morin

Boivin-Welch

et al. 2015

PeerJ

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The proton pump vacuolar (V)-ATPase is the driving force that mediates the concentration of cationic drugs (weak bases) in the late endosome-lysosome continuum; secondary cell reactions include the protracted transformation of enlarged vacuoles into autophagosomes. We used the inherently fluorescent tertiary amine quinacrine in murine models to further assess the accumulation and signaling associated with cation trapping. Primary fibroblasts concentrate quinacrine ∼5,000-fold from their culture medium (KM 9.8 µM; transport studies). The drug is present in perinuclear granules that are mostly positive for Rab7 and LAMP1 (microscopy). Both drug uptake and retention are extensively inhibited by treatments with the V-ATPase inhibitor bafilomycin A1. The H+ ionophore monensin also prevented quinacrine concentration by fibroblasts. However, inhibition of plasma membrane transporters or of the autophagic process with spautin-1 did not alter quinacrine transport parameters. Ancillary experiments did not support that low micromolar concentrations of quinacrine are substrates for organic cation transporters-1 to -3 or P-glycoprotein. The secondary autophagy induced by quinacrine in cells may derive from the accumulation of incompetent autophagolysosomes, as judged from the accumulation of p62/SQSTM1 and LC3 II (immunoblots). Accordingly, protracted lysosomogenesis is evidenced by increased expression of LAMP1 and LAMP2 in quinacrine-treated fibroblasts (48 h, immunoblots), a response that follows the nuclear translocation of the lysosomal genesis transcription factor TFEB and upregulation of LAMP1 and −2 mRNAs (24 h). Quinacrine administration to live mice evidenced variable distribution to various organs and heterogeneous accumulation within the lung (stereo-microscopy, extraction). Dose-dependent in vivo autophagic and lysosomal accumulation was observed in the lung (immunoblots). No evidence has been found for transport or extrusion mechanisms modulating the cellular uptake of micromolar quinacrine at the plasma membrane level. As shown in vitro and in vivo, V-ATPase-mediated cation sequestration is associated, above a certain threshold, to autophagic flux inhibition and feed-back lysosomogenesis.

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“…Inflammatory neutrophils also produce and release an array of specific soluble mediators of inflammation. Eicosanoids, cytokines, and chemokines [ 6 - 8 ] may each influence the course of immune reactions in a multi-pronged fashion, by soliciting and regulating different cell types involved in the normal development and resolution of an effective inflam-matory response [ 9 ]. Aging reportedly affects important receptor-driven functions of neutrophils [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A2A receptor

Laflamme

Mailhot

Pouliot

2017

Aging

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Aging is accompanied by an increase in markers of innate immunity. How aging affects neutrophil functions remains of debate. The adenosine A2A receptor (A2AR), essential to the resolution of inflammation, modulates neutrophil functions. We sought to determine whether or not A2AR protects against the effects of aging. We monitored neutrophil influx, viability, and activation as well as cytokine accumulation in wild-type (WT) and A2AR-knockout mice (KO) at three different ages.Several readouts decreased with aging: neutrophil counts in dorsal air pouches (by up to 55%), neutrophil viability (by up to 56%), elastase and total protein in exudates (by up to 80%), and local levels of cytokines (by up to 90%). Each of these parameters was significantly more affected in A2AR-KO mice. CXCL1-3 levels were largely unaffected. The effects of aging were not observed systemically. Preventing neutrophil influx into the air pouch caused a comparable cytokine pattern in young WT mice. Gene expression (mRNA) in leukocytes was affected, with CXCL1 and CCL4 increasing and with TNF and IL-1∝ decreasing.Conclusion: Aging has deleterious effects on the acute inflammatory response and neutrophil-related activities, and defective migration appears as an important factor. A functional A2AR signaling pathway delays some of these.

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Evidence of impairment of normal inflammatory reaction by a high-fat diet

Cited by 3 publications

References 48 publications

TNF‐α expression in neutrophils and its regulation by glycogen synthase kinase‐3: A potentiating role for lithium

TNF‐α expression in neutrophils and its regulation by glycogen synthase kinase‐3: A potentiating role for lithium

Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models

Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A2A receptor

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