About: Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages

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An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages
Creator	Chen, S Yu, Y Wu, Y Baumann, T Beckers, J Eickelberg, O Irmler, M Kammerl, I Meiners, S Overkleeft, H Stoeger, T Vosyka, O München, Helmholtz
Source	PMC
abstract	The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes involved in shaping adaptive immune responses, but their role in innate immune signaling is still elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages, highly specialized tissue macrophages of the alveolar lung surface. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNγ transcriptionally induced all three immunoproteasome subunits, low molecular mass protein 2 (LMP2), LMP7 and multicatalytic endopeptidase complex-like 1, which was accompanied by increased immunoproteasome activity in M1 cells. Deficiency of LMP7 had no effect on the LPS/IFNγ-triggered M1 profile indicating that immunoproteasome function is dispensable for classical alveolar macrophage activation. In contrast, IL-4 triggered alternative (M2) activation of primary alveolar macrophages was accompanied by a transcriptionally independent amplified expression of LMP2 and LMP7 and an increase in immunoproteasome activity. Alveolar macrophages from LMP7 knockout mice disclosed a distorted M2 profile upon IL-4 stimulation as characterized by increased M2 marker gene expression and CCL17 cytokine release. Comparative transcriptome analysis revealed enrichment of IL-4-responsive genes and of genes involved in cellular response to defense, wounding and inflammation in LMP7-deficient alveolar macrophages indicating a distinct M2 inflammation resolving phenotype. Moreover, augmented M2 polarization was accompanied by amplified AKT/STAT6 activation and increased RNA and protein expression of the M2 master transcription factor interferon regulatory factor 4 in LMP7(−/−) alveolar macrophages. IL-13 stimulation of LMP7-deficient macrophages induced a similar M2-skewed profile indicative for augmented signaling via the IL-4 receptor α (IL4Rα). IL4Rα expression was generally elevated only on protein but not RNA level in LMP7(−/−) alveolar macrophages. Importantly, specific catalytic inhibition with an LMP7-specific proteasome inhibitor confirmed augmented IL-4-mediated M2 polarization of alveolar macrophages. Our results thus suggest a novel role of immunoproteasome function for regulating alternative activation of macrophages by limiting IL4Rα expression and signaling.
has issue date	2016-03-18(xsd:dateTime)
bibo:doi	10.1038/cdd.2016.3
bibo:pmid	26990663
has license	no-cc
sha1sum (hex)	56f99487f13b5e7b13e7983c2913188c41ad0761
schema:url	https://doi.org/10.1038/cdd.2016.3
resource representing a document's title	Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages
has PubMed Central identifier	PMC4987736
has PubMed identifier	26990663
schema:publication	Cell Death Differ
resource representing a document's body	covid:56f99487f13b5e7b13e7983c2913188c41ad0761#body_text
is schema:about of	named entity 'IL4Rα' named entity 'IL-4 receptor' named entity 'transcription factor' named entity 'protein' named entity 'LMP7' named entity 'LMP2' named entity 'immunoproteasome' named entity 'AKT' named entity 'IL-4' named entity 'proteasomes' named entity 'IL4Rα' named entity 'protein' named entity 'LPS' named entity 'immunoproteasome' named entity 'gene expression' named entity 'adaptive immune responses' named entity 'alveolar' named entity 'alveolar macrophages' named entity 'immunoproteasome' named entity 'LMP7' named entity 'high levels' named entity 'Arg1' named entity 'protein' named entity 'macrophages' named entity 'LMP7' named entity 'DMSO' named entity 'lung' named entity 'LMP7' named entity 'St. Louis' named entity 'ATP' named entity 'alveolar macrophages' named entity 'gene expression' named entity 'LMP2' named entity 'immunoproteasome' named entity 'Houston' named entity 'RPMI' named entity 'pulmonary fibrosis' named entity 'immunoproteasome' named entity '37°C' named entity 'host defense' named entity 'lysates' named entity 'active-site' named entity 'IL-4' named entity 'LMP7' named entity 'HEPES' named entity 'pro-inflammatory' named entity 'Th2' named entity 'Ccl17' named entity 'Arg1' named entity 'CDC' named entity 'immune surveillance' named entity 'IL-4 receptor' named entity 'chemokine' named entity 'tissue macrophages' named entity 'innate immune cell' named entity 'DMSO' named entity 'sodium deoxycholate' named entity 'immunoblotting' named entity 'pulmonary fibrosis' named entity 'threonine' named entity 'macrophages' named entity 'proof-of-concept' named entity 'QPCR' named entity 'IRF4' named entity 'LMP7' named entity 'immunoproteasome' named entity 'BALB' named entity 'immunoproteasome' named entity 'immunoproteasome'

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