Alveolar and intraparenchymal proteasome in sarcoidosis

Sixt, Stephan Urs; Costabel, Ulrich; Bonella, Francesco; Grunert, K.; Alami, Ramzi S.; Hakenbeck, Jan; Bauer, Peter; Dahlmann, Burkhardt; Schmid, K. W.; Wohlschlaeger, Jeremias

doi:10.1016/j.rmed.2014.09.004

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…1c ). This is in line with a recent study that demonstrated expression of LMP2 and LMP7 in lung granulomas of sarcoidosis patients 24 . Our in vitro data show that primary alveolar type II cells and fibroblasts have the capability to express immunoproteasomes after IFNγ stimulation, thus enabling immunoproteasome-dependent antigen presentation.…”

Section: Discussionsupporting

confidence: 93%

“…While other studies have examined total levels of immunoproteasomes in human tissue, whole rat lungs, and in LCMV-infected mouse lungs and other organs 19 20 21 22 23 , cell-specific expression in the lung has not yet been investigated 23 24 . Here, we show that the immunoproteasomal subunit LMP2 is expressed at low basal levels in lung parenchymal cells (alveolar type I and II cells, fibroblasts) and the bronchial epithelium but strongly expressed in alveolar macrophages ( Figs.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Immunoproteasome Function in the Lung

Keller

Vosyka

Takenaka

et al. 2015

Sci Rep

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Impaired immune function contributes to the development of chronic obstructive pulmonary disease (COPD). Disease progression is further exacerbated by pathogen infections due to impaired immune responses. Elimination of infected cells is achieved by cytotoxic CD8+ T cells that are activated by MHC I-mediated presentation of pathogen-derived antigenic peptides. The immunoproteasome, a specialized form of the proteasome, improves generation of antigenic peptides for MHC I presentation thereby facilitating anti-viral immune responses. However, immunoproteasome function in the lung has not been investigated in detail yet. In this study, we comprehensively characterized the function of immunoproteasomes in the human and murine lung. Parenchymal cells of the lung express low constitutive levels of immunoproteasomes, while they are highly and specifically expressed in alveolar macrophages. Immunoproteasome expression is not altered in whole lung tissue of COPD patients. Novel activity-based probes and native gel analysis revealed that immunoproteasome activities are specifically and rapidly induced by IFNγ treatment in respiratory cells in vitro and by virus infection of the lung in mice. Our results suggest that the lung is potentially capable of mounting an immunoproteasome-mediated efficient adaptive immune response to intracellular infections.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Regulation of Immunoproteasome Function in the Lung

Keller

Vosyka

Takenaka

et al. 2015

Sci Rep

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“…A recent study suggested elevated expression of immunoproteasome subunits in alveolar macrophages in patients with sarcoidosis. 54 Preliminary data of our group also suggest increased protein levels of LMP7 in BAL cells isolated from fibrotic lungs of bleomycin instilled mice. Future studies using LMP7-deficient mice will investigate the functional relevance of LMP7 activity for the course of bleomycin-triggered pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 72%

Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages

et al. 2016

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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. The immunoproteasome is a specialized type of proteasome and constitutively active in immune cells, whereas standard proteasomes are expressed in all non-immune cells. Similar to the standard 20S proteasome, immunoproteasomes are composed of two outer α-rings and two inner β-rings of seven subunits each 1 but contain a different set of IFNγ-inducible

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“…17 Misfolding and aggregation of serum amyloid A (SAA) might play an important role in sarcoidosis. 19 The microarray analysis of BALf cells performed by Gharib et al showed an important relationship between adaptive immunity and the proteasomal apparatus in this disease. 19 The microarray analysis of BALf cells performed by Gharib et al showed an important relationship between adaptive immunity and the proteasomal apparatus in this disease.…”

Section: Discussionmentioning

confidence: 96%

“…18 Immunoproteasome was markedly expressed in sarcoidosis tissues, its expression in BALf was disease-stage dependent. 19 The microarray analysis of BALf cells performed by Gharib et al showed an important relationship between adaptive immunity and the proteasomal apparatus in this disease. 20 Our analysis confirmed the increased expression of mRNA for interferon gamma (IFNG), a key regulator of the immunoproteasome as well as proteasome subunit beta 9 (PSMB9), PSMB10 and not significantly for PSMB8 in BALf cells of sarcoidosis compared to IPF patients.…”

Section: Probe Identifier Gene P-value Adjusted P-value Fold Changementioning

confidence: 96%

mRNA expression profile of bronchoalveolar lavage fluid cells from patients with idiopathic pulmonary fibrosis and sarcoidosis

Paplińska-Goryca

Goryca

Misiukiewicz-Stępień

et al. 2019

Eur J Clin Investigation

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Alveolar and intraparenchymal proteasome in sarcoidosis

Abstract: Patients with active sarcoidosis but not healthy controls demonstrate immunoproteasome in the lung tissue and in granulomas. Thus, the putative immune response in sarcoidosis may be mediated or sustained by the proteasomal system.

Cited by 7 publications

References 29 publications

Regulation of Immunoproteasome Function in the Lung

Regulation of Immunoproteasome Function in the Lung

Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages

mRNA expression profile of bronchoalveolar lavage fluid cells from patients with idiopathic pulmonary fibrosis and sarcoidosis

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