scholarly journals Intrinsic Properties of Brown and White Adipocytes Have Differential Effects on Macrophage Inflammatory Responses

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Louisa Dowal ◽  
Pooja Parameswaran ◽  
Sarah Phat ◽  
Syamala Akella ◽  
Ishita Deb Majumdar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Inflammatory Responses ◽  
Low Grade ◽  
Brown Adipocytes ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Inflammatory Status ◽  
White Adipocytes ◽  
Inflammatory Profile

Obesity is marked by chronic, low-grade inflammation. Here, we examined whether intrinsic differences between white and brown adipocytes influence the inflammatory status of macrophages. White and brown adipocytes were characterized by transcriptional regulation of UCP-1, PGC1α, PGC1β, and CIDEA and their level of IL-6 secretion. The inflammatory profile of PMA-differentiated U937 and THP-1 macrophages, in resting state and after stimulation with LPS/IFN-gamma and IL-4, was assessed by measuring IL-6 secretion and transcriptional regulation of a panel of inflammatory genes after mono- or indirect coculture with white and brown adipocytes. White adipocyte monocultures show increased IL-6 secretion compared to brown adipocytes. White adipocytes cocultured with U937 and THP-1 macrophages induced a greater increase in IL-6 secretion compared to brown adipocytes cocultured with both macrophages. White adipocytes cocultured with macrophages increased inflammatory gene expression in both types. In contrast, macrophages cocultured with brown adipocytes induced downregulation or no alterations in inflammatory gene expression. The effects of adipocytes on macrophages appear to be independent of stimulation state. Brown adipocytes exhibit an intrinsic ability to dampen inflammatory profile of macrophages, while white adipocytes enhance it. These data suggest that brown adipocytes may be less prone to adipose tissue inflammation that is associated with obesity.

scholarly journals P050 Effect of biological treatments (anti-TNFs) in the creeping fat of Crohn’s disease patients

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S158-S159
Author(s):  
D Montfort-Ferré ◽  
C Serena ◽  
M Millan ◽  
A Boronat-Toscano ◽  
E Maymó-Masip ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Low Grade ◽  
Inflammatory Gene Expression ◽  
Histological Studies ◽  
Inflammatory Gene ◽  
Inflammatory Status ◽  
Mesenteric Fat

Abstract Background Crohn’s disease (CD) is characterized by persistent inflammation and ulcerations at the small or large bowel, provoking chronic low-grade systemic inflammation. Adipose tissue (AT) is believed to play an active role in the pathogenesis of CD, as the expansion of mesenteric fat attached to the inflamed segments of the intestine, also known as “creeping fat,” is a hallmark of the disease that seems to be directly related to disease activity. We demonstrated that adipose-stem cells (ASC) isolated from the creeping fat of CD patients showed a proinflammatory phenotype and increased the proliferation, migration, and phagocytic capacities of these cells. Taking into account the widely described effects of TNFalpha on the biology and functionality of adipocytes, we believe that biological therapies based on anti-TNF agents modify the inflammatory status of creeping fat. In this context, the effect of anti-TNF treatment on mesenteric fat is poorly studied, and the results are divergent. Methods Creeping fat biopsies were obtained from active CD patients that underwent surgery for symptomatic complications: 10 patients were on anti-TNF therapy (at least 6-months prior to surgery) and 10 patients never received any biological therapy. The groups were comparable in age, sex, and body mass index. We isolated from AT biopsies: AT explants, ASC, and adipose tissue macrophages (ATM). Adipose tissue was fixed in 10% phosphate-buffered formalin and embedded in paraffin for histological studies. The proliferation of ASC was performed using the CellTraceTM Violet Cell proliferation kit using flow cytometry and the cell migration of ASC was analyzed using a Tranwell system (8 mmpore polycarbonate membrane). Results Histological studies revealed that AT of patients treated with anti-TNF therapy recovered adipocytes morphology and showed lower infiltration of immune cells. Interestingly, we found a significant decrease in the gene expression of pro-inflammatory cytokines (IL1B, IL6, TNFA) in the creeping fat of CD patients treated with anti-TNF (Figure 1A). Furthermore, ATMs isolated from patients treated with anti-TNF showed a significant decrease in the gene expression of antigen-presenting markers (CD74, CIITa, HLA-DPB and HLA-DM) (Figure 1B). To note, ASC isolated from patients with anti-TNF therapy has significantly decreased their proliferation and migration capacities as well as the pro-inflammatory gene expression. Moreover, the anti-inflammatory gene expression and secretion were significantly increased in these cells (Figure 1C). Conclusion Anti-TNF therapies impact on the creeping fat of CD patients improving the phenotype of this tissue and this may cause a beneficial effect on CD.

scholarly journals Maternal high-fat diet induces sex-specific changes to glucocorticoid and inflammatory signaling in response to corticosterone and lipopolysaccharide challenge in adult rat offspring

2019 ◽  
Author(s):  
Sanoji Wijenayake ◽  
Mouly F. Rahman ◽  
Christine M.W. Lum ◽  
Wilfred C. De Vega ◽  
Aya Sasaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Inflammatory Responses ◽  
Physiological Stress ◽  
High Fat ◽  
Inflammatory Gene Expression ◽  
Inflammatory Genes ◽  
Inflammatory Gene ◽  
Rat Offspring

ABSTRACTBackgroundAcute elevations in endogenous corticosterone (CORT) with psychosocial stress or exogenous administration potentiate inflammatory gene expression. Maternal obesity as a result of high-fat diet (HFD) consumption has been linked to higher basal levels of neuroinflammation, including increased expression of pro-inflammatory genes in the amygdala. These findings suggest that exposure to maternal HFD may elicit pro-inflammatory responses in the presence of an immune stressor such as lipopolysaccharide (LPS), a component of gram-negative bacteria, as well as acute elevated CORT.MethodsRat offspring were exposed to maternal HFD or control diet (CHD) throughout pre and postnatal development until weaning, when all offspring were provided CHD until adulthood. In adulthood, offspring were ‘challenged’ with administration of exogenous CORT, to simulate an acute physiological stress, LPS, to induce an immune stress, or both. qPCR was used to measure transcript abundance of CORT receptors and downstream inflammatory genes in the amygdala, hippocampus and prefrontal cortex, brain regions that mediate neuroendocrine and behavioral responses to stress.ResultsHFD female offspring exhibited elevations in anti-inflammatory transcripts, whereas HFD male offspring responded with greater pro-inflammatory gene expression to simultaneous CORT and LPS administration.ConclusionsThese findings suggest that exposure to maternal HFD leads to sex-specific alterations that may alter inflammatory responses in the brain, possibly as an adaptive response to basal inflammation.

scholarly journals Astragaloside IV Inhibits NF-κB Activation and Inflammatory Gene Expression in LPS-Treated Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Wei-Jian Zhang ◽  
Balz Frei
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cellular Adhesion ◽  
Mrna Levels ◽  
Astragaloside Iv ◽  
Chinese Medicinal Herb ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

In this study we investigated the role of astragaloside IV (AS-IV), one of the major active constituents purified from the Chinese medicinal herbAstragalus membranaceus, in LPS-induced acute inflammatory responses in micein vivoand examined possible underlying mechanisms. Mice were assigned to four groups: vehicle-treated control animals; AS-IV-treated animals (10 mg/kg b.w. AS-IV daily i.p. injection for 6 days); LPS-treated animals; and AS-IV plus LPS-treated animals. We found that AS-IV treatment significantly inhibited LPS-induced increases in serum levels of MCP-1 and TNF by 82% and 49%, respectively. AS-IV also inhibited LPS-induced upregulation of inflammatory gene expression in different organs. Lung mRNA levels of cellular adhesion molecules, MCP-1, TNFα, IL-6, and TLR4 were significantly attenuated, and lung neutrophil infiltration and activation were strongly inhibited, as reflected by decreased myeloperoxidase content, when the mice were pretreated with AS-IV. Similar results were observed in heart, aorta, kidney, and liver. Furthermore, AS-IV significantly suppressed LPS-induced NF-κB and AP-1 DNA-binding activities in lung and heart. In conclusion, our data provide newin vivoevidence that AS-IV effectively inhibits LPS-induced acute inflammatory responses by modulating NF-κB and AP-1 signaling pathways. Our results suggest that AS-IV may be useful for the prevention or treatment of inflammatory diseases.

Abstract 361: Oxidized Phospholipids Are Proinflammatory and Proatherogenic

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Xuchu Que ◽  
Calvin Yeang ◽  
Ming-Yow Hung ◽  
Fumihiro Yamaguchi ◽  
Cody J Diehl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Biological Effects ◽  
Progressive Increase ◽  
Oxidized Phospholipids ◽  
Single Chain ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Novel Strategy

Oxidized phospholipids (OxPL) are ubiquitously generated during inflammation, and found on apoptotic cells, OxLDL, and Lp(a). They facilitate uptake of OxLDL by macrophages (Mac) and mediate cellular inflammatory responses. The E06 natural IgM binds to the PC of OxPL, neutralizing biological effects and inhibiting OxLDL uptake by Mac. To determine the role of OxPL in atherogenesis, we generated transgenic mice expressing a single chain variant (scFv) of E06 in Ldlr background (E06-Tg). E06-scFv was secreted into plasma, bound to OxLDL and had sufficient titer to inhibit OxLDL uptake into Mac. E06-Tg or Ldlr mice were fed 1% Chol diet for 4, 7 or 12 months (n=12-15 mice/group). Plasma Chol was ~ 1600 mg/dL in all mice. Atherosclerosis decreased in E06-Tg mice: En face lesions decreased 57%, 34% and 28%, and aortic root lesions decreased 55%, 41% and 26% at 4, 7 and 12-months, respectively. OxLDL uptake by Macs was decreased: Thus, in E06-Tg mice, the uptake by peritoneal Mac of fluorescently-labeled OxLDL injected ip was decreased ~ 50%, as was peritoneal Mac Chol content. As Macs secrete E06-scFv, we performed BMT from E06-Tg donors into irradiated Ldlr recipients (n=10-12): This also decreased lesions 31% compared to BMT from control donors, even though plasma titers of E06-scFv were ~10% of Tg mice. Overexpression of E06-scFv was anti-inflammatory: Thus, in E06-Tg mice, both peritoneal and aortic wall resident macrophages exhibited decreased inflammatory gene expression, and phenotypic switches from M1 to M2 analyzed by RNAseq and FACS. Further, in E06-Tg mice, plasma SAA levels were reduced 32%, and hepatic steatosis was also decreased (-50% in both TG and Chol), as was hepatic inflammatory gene expression. Finally, E06-scFv attenuated both a progressive increase in aortic valve gradient (via echocardiography) and calcification in aged Ldlr mice. The E06-scFv lacks functional effects of an intact antibody other than the ability to “neutralize” OxPL. Thus, these data demonstrate that OxPL are profoundly proatherogenic and proinflammatory, which E06 counteracts in vivo . Neutralizing OxPL may therefore reduce the progression of atherosclerosis and cardiovascular events and more generally, represents a novel strategy to safely attenuate inflammation.

scholarly journals HDAC3 Regulates Gingival Fibroblast Inflammatory Responses in Periodontitis

2019 ◽  
Vol 99 (1) ◽  
pp. 98-106 ◽  
Author(s):  
K.B. Lagosz ◽  
A. Bysiek ◽  
J.M. Macina ◽  
G.P. Bereta ◽  
M. Kantorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Mediators ◽  
Histone Deacetylases ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Gingival Fibroblast ◽  
Mrna Levels ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Inflammatory Activation

Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis–inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs ( IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis–infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis–induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.

scholarly journals Systemic LPS induces spinal inflammatory gene expression and impairs phrenic long-term facilitation following acute intermittent hypoxia

2013 ◽  
Vol 114 (7) ◽  
pp. 879-887 ◽  
Author(s):  
A. G. Huxtable ◽  
S. M. C. Smith ◽  
S. Vinit ◽  
J. J. Watters ◽  
G. S. Mitchell
Keyword(s):  
Gene Expression ◽  
Systemic Inflammation ◽  
Intermittent Hypoxia ◽  
Neural Control ◽  
Low Grade ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Long Term Facilitation ◽  
The Impact

Although systemic inflammation occurs in most pathological conditions that challenge the neural control of breathing, little is known concerning the impact of inflammation on respiratory motor plasticity. Here, we tested the hypothesis that low-grade systemic inflammation induced by lipopolysaccharide (LPS, 100 μg/kg ip; 3 and 24 h postinjection) elicits spinal inflammatory gene expression and attenuates a form of spinal, respiratory motor plasticity: phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia (AIH; 3, 5 min hypoxic episodes, 5 min intervals). pLTF was abolished 3 h (vehicle control: 67.1 ± 27.9% baseline; LPS: 3.7 ± 4.2%) and 24 h post-LPS injection (vehicle: 58.3 ± 17.1% baseline; LPS: 3.5 ± 4.3%). Pretreatment with the nonsteroidal anti-inflammatory drug ketoprofen (12.5 mg/kg ip) restored pLTF 24 h post-LPS (55.1 ± 12.3%). LPS increased inflammatory gene expression in the spleen and cervical spinal cord (homogenates and isolated microglia) 3 h postinjection; however, all molecules assessed had returned to baseline by 24 h postinjection. At 3 h post-LPS, cervical spinal iNOS and COX-2 mRNA were differentially increased in microglia and homogenates, suggesting differential contributions from spinal cells. Thus LPS-induced systemic inflammation impairs AIH-induced pLTF, even after measured inflammatory genes returned to normal. Since ketoprofen restores pLTF even without detectable inflammatory gene expression, “downstream” inflammatory molecules most likely impair pLTF. These findings have important implications for many disease states where acute systemic inflammation may undermine the capacity for compensatory respiratory plasticity.

scholarly journals Prior hypoxia exposure enhances murine microglial inflammatory gene expression in vitro without concomitant H3K4me3 enrichment

2020 ◽  
Author(s):  
Elizabeth A. Kiernan ◽  
Andrea C. Ewald ◽  
Jonathan N. Ouellette ◽  
Tao Wang ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Immunoprecipitation ◽  
Sleep Disordered Breathing ◽  
Inflammatory Responses ◽  
Hypoxic Exposure ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Hypoxia Exposure ◽  
Chromatin Immunoprecipitation Sequencing

ABSTRACTHypoxia is a component of multiple disorders, including stroke and sleep-disordered breathing, that often precede or are comorbid with neurodegenerative diseases. However, little is known about how hypoxia affects the ability of microglia, resident CNS macrophages, to respond to subsequent inflammatory challenges that are often present during neurodegenerative processes. We therefore tested the hypothesis that hypoxia would enhance or “prime” microglial pro-inflammatory gene expression in response to a later inflammatory challenge without programmatically increasing basal levels of pro-inflammatory cytokine expression. To test this, we pre-exposed immortalized N9 and primary microglia to hypoxia (1% O2) for 16 hrs and then challenged them with pro-inflammatory lipopolysaccharide (LPS) either immediately or 3-6 days following hypoxic exposure. We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to analyze primed microglial inflammatory gene expression and modifications to histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of primed genes. We found that microglia exhibited enhanced responses to LPS 3 days and 6 days post-hypoxia. Surprisingly however, the majority of primed genes were not enriched for H3K4me3 acutely following hypoxia exposure. Using the bioinformatics tool MAGICTRICKS and reversible pharmacological inhibition, we found that primed genes required the transcriptional activities of NF-ĸB. These findings provide evidence that hypoxia pre-exposure could lead to persistent and aberrant inflammatory responses in the context of CNS disorders.

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