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    <pageNumber>14</pageNumber>
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    <volume>15</volume>
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    <publisherName>Frontiers Media S.A.</publisherName>
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    <publishedDate>2024-07-10</publishedDate>
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    <title language="eng">Dysregulated cytokine and oxidative response in hyper-glycolytic monocytes in obesity</title>
    <abstract language="eng">Introduction: Obesity is associated with a plethora of health complications, including increased susceptibility to infections or decreased vaccine efficacy, partly due to dysregulated immune responses. Monocytes play a crucial role in innate immunity, yet their functional alterations in obesity remain poorly understood.&#13;
&#13;
Methods: Here, we employed proteomic and metabolomic analyses to investigate monocyte characteristics in individuals with overweight, obesity, impaired glucose tolerance (IGT), and type 2 diabetes (T2D), compared to lean donors.&#13;
&#13;
Results and discussion: Our results revealed distinct molecular signatures in monocytes from individuals with obesity, with significant alterations in pathways related to metabolism, cellular migration, and phagocytosis. Moreover, LPS-induced activation of monocytes unveiled heightened metabolic reprogramming towards glycolysis in subjects with obesity accompanied by dysregulated cytokine responses and elevated oxidative stress. Additionally, monocytes from donors with obesity exhibited increased lipid droplet accumulation. These findings shed light on the immunometabolic dysregulation underlying obesity-associated immune dysfunction, highlighting potential targets for therapeutic intervention.</abstract>
    <parentTitle language="eng">Frontiers in Immunology</parentTitle>
    <identifier type="issn">1664-3224</identifier>
    <identifier type="doi">10.3389/fimmu.2024.1416543</identifier>
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    <author>
      <firstName>Veselina</firstName>
      <lastName>Radushev</lastName>
    </author>
    <author>
      <firstName>Isabel</firstName>
      <lastName>Karkossa</lastName>
    </author>
    <author>
      <firstName>Janina</firstName>
      <lastName>Berg</lastName>
    </author>
    <author>
      <firstName>Martin von</firstName>
      <lastName>Bergen</lastName>
    </author>
    <author>
      <firstName>Beatrice</firstName>
      <lastName>Engelmann</lastName>
    </author>
    <author>
      <firstName>Ulrike</firstName>
      <lastName>Rolle-Kampczyk</lastName>
    </author>
    <author>
      <firstName>Matthias</firstName>
      <lastName>Blüher</lastName>
    </author>
    <author>
      <firstName>Ulf</firstName>
      <lastName>Wagner</lastName>
    </author>
    <author>
      <firstName>Kristin</firstName>
      <lastName>Schubert</lastName>
    </author>
    <author>
      <firstName>Manuela</firstName>
      <lastName>Rossol</lastName>
    </author>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>monocytes</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>immunometabolism</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>respiratory burst</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>obesity</value>
    </subject>
    <subject>
      <language>eng</language>
      <type>uncontrolled</type>
      <value>IL-8</value>
    </subject>
    <collection role="Import" number="import">Import</collection>
    <collection role="institutes" number="8312">FG Molekulare Immunologie</collection>
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  <doc>
    <id>33955</id>
    <completedYear/>
    <publishedYear>2024</publishedYear>
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    <language>eng</language>
    <pageFirst/>
    <pageLast/>
    <pageNumber>19</pageNumber>
    <edition/>
    <issue>845</issue>
    <volume>17</volume>
    <type>article</type>
    <publisherName>American Association for the Advancement of Science (AAAS)</publisherName>
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    <completedDate>2024-08-20</completedDate>
    <publishedDate>--</publishedDate>
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    <title language="eng">Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes</title>
    <abstract language="eng">Hypoxia and low glucose abundance often occur simultaneously at sites of inflammation. In monocytes and macrophages, glucose-oxygen deprivation stimulates the assembly of the NLRP3 inflammasome to generate the proinflammatory cytokine IL-1β. We found that concomitant glucose deprivation and hypoxia activated the NLRP3 inflammasome by constraining the function of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate kinase pathway. HMGCR is involved in the synthesis of geranylgeranyl pyrophosphate (GGPP), which is required for the prenylation and lipid membrane integration of proteins. Under glucose-oxygen deprivation, GGPP synthesis was decreased, leading to reduced prenylation of the small GTPase Rac1, increased binding of nonprenylated Rac1 to the scaffolding protein IQGAP1, and enhanced activation of the NLRP3 inflammasome. In response to restricted oxygen and glucose supply, patient monocytes with a compromised mevalonate pathway due to mevalonate kinase deficiency or Muckle-Wells syndrome released more IL-1β than did control monocytes. Thus, reduced GGPP synthesis due to inhibition of HMGCR under glucose-oxygen deprivation results in proinflammatory innate responses, which are normally kept in check by the prenylation of Rac1. We suggest that this mechanism is also active in inflammatory autoimmune conditions.</abstract>
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    <language>eng</language>
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    <pageNumber>15</pageNumber>
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    <title language="eng">Triclosan and its alternatives, especially chlorhexidine, modulate macrophage immune response with distinct modes of action</title>
    <abstract language="eng">Since European regulators restricted the use of bacteriocidic triclosan (TCS), alternatives for TCS are emerging. Recently, TCS has been shown to reprogram immune metabolism, trigger the NLRP3 inflammasome, and subsequently the release of IL-1β in human macrophages, but data on substitutes is scarce. Hence, we aimed to examine the effects of TCS compared to its alternatives at the molecular level in human macrophages. LPS-stimulated THP-1 macrophages were exposed to TCS or its substitutes, including benzalkonium chloride, benzethonium chloride, chloroxylenol, chlorhexidine (CHX) and cetylpyridinium chloride, with the inhibitory concentration (IC10-value) of cell viability to decipher their mode of action. TCS induced the release of the pro-inflammatory cytokine TNF and high level of IL-1β, suggesting the activation of the NLRP3-inflammasome, which was confirmed by non-apparent IL-1β under the NLRP3-inhibitor MCC950 treatment d. While IL-6 release was reduced in all treatments, the alternative CHX completely abolished the release of all investigated cytokines. To unravel the underlying molecular mechanisms, we used untargeted LC-MS/MS-based proteomics. TCS and CHX showed the strongest cellular response at the protein and signalling pathway level, whereby pathways related to metabolism, translation, cellular stress and migration were mainly affected but to different proposed modes of action. TCS inhibited mitochondrial electron transfer and affected phagocytosis. In contrast, in CHX-treated cells, the translation was arrested due to stress conditions, resulting in the formation of stress granules. Mitochondrial (e.g. ATP5F1D, ATP5PB, UQCRQ) and ribosomal (e.g. RPL10, RPL35, RPS23) proteins were revealed as putative key drivers. Furthermore, we have demonstrated the formation of podosomes by CHX, potentially involved in ECM degradation. Our results exhibit modulation of the immune response in macrophages by TCS and its substitutes and illuminated underlying molecular effects. These results illustrate critical processes involved in the modulation of macrophages' immune response by TCS and its alternatives, providing information essential for hazard assessment.</abstract>
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