Impairment of Immunoproteasome Function by Cigarette Smoke and in Chronic Obstructive Pulmonary Disease

Kammerl, Ilona; Dann, Angela; Mossina, Alessandra; Brech, Dorothee; Lukas, Christina; Vosyka, Oliver; Nathan, Petra; Conlon, Thomas M.; Wagner, Darcy E.; Overkleeft, Hermen S.; Prasse, Antje; Rosas, Iván O.; Straub, Tobias; Krauss‐Etschmann, Susanne; Königshoff, Mélanie; Preißler, Gerhard; Winter, Hauke; Lindner, Michael; Hatz, Rudolf; Behr, Jürgen; Heinzelmann, Katharina; Yildirim, Ali Önder; Noeßner, Elfriede; Eickelberg, Oliver; Meiners, Silke

doi:10.1164/rccm.201506-1122oc

Cited by 43 publications

(48 citation statements)

References 52 publications

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“…Further dysregulation of macrophage function in COPD was documented by significant downregulation of molecules associated with antigen presentation, especially MHC class I. This finding is in accordance with previous studies linking down-regulation of surface MHC class I in COPD with impaired immunoproteasome activity (Hodge et al, 2011;Kammerl et al, 2016).…”

Section: Discussionsupporting

confidence: 91%

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Baßler

Fujii

Kapellos

et al. 2020

Preprint

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Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular mechanisms of this disease are far from being understood. Here, we characterize and classify the cellular composition within the alveolar space and peripheral blood of COPD patients and control donors using a clinically applicable single-cell RNA-seq technology corroborated by advanced computational approaches for: machine learning-based cell-type classification, identification of differentially expressed genes, prediction of metabolic changes, and modeling of cellular trajectories within a patient cohort. These high-resolution approaches revealed: massive transcriptional plasticity of macrophages in the alveolar space with increased levels of invading and proliferating cells, loss of MHC expression, reduced cellular motility, altered lipid metabolism, and a metabolic shift reminiscent of mitochondrial dysfunction in COPD patients. Collectively, single-cell omics of multi-tissue samples was used to build the first cellular and molecular framework for COPD pathophysiology as a prerequisite to develop molecular biomarkers and causal therapies against this deadly disease.

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Section: Discussionsupporting

confidence: 91%

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Baßler

Fujii

Kapellos

et al. 2020

Preprint

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“…COPD is a major cause of morbidity and mortality globally, and knowledge about its pathogenesis has increased substantially over the past decade (9,10). The primary risk factor for COPD is prolonged cigarette smoking (11). Another risk factor for COPD is chronic environmental exposure to toxic atmospheric pollutants, including PM (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of stemonine on particulate matter 2.5‑induced chronic obstructive pulmonary disease in mice

Zhang

Sun

et al. 2017

Exp Ther Med

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Abstract. Particulate matter 2.5 (PM 2.5 ) is a growing concern worldwide due to its association with respiratory diseases, including chronic obstructive pulmonary disease (COPD). Stemonine, a traditional Chinese herb, has been demonstrated to exhibit anti-inflammatory and antioxidant properties, making it a potential drug for the treatment of respiratory diseases. The therapeutic effects of stemonine on mice with PM 2.5 -induced COPD were investigated in the present study. Kunming mice were randomly divided into the following five groups (n=10/group): Control, model, low-dose stemonine, moderate-dose stemonine and high-dose stemonine. The model mice received an intranasal instillation of PM 2.5 suspension (40 mg/kg). The levels of specific enzymes, markers of oxidative stress, and the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured in the bronchoalveolar lavage fluid of the mice using ELISA kits. Hematoxylin and eosin staining was performed to determine inflammatory changes to the lung tissue. It was demonstrated that stemonine could significantly alleviate lung injury by decreasing the levels of enzymes and cytokines associated with inflammation and oxidative stress in a dose-dependent manner. In addition, stemonine dose-dependently increased the amount of superoxide dismutase. These results suggest that stemonine reduces lung inflammation in mice with PM 2.5 -induced COPD, providing a novel approach for the treatment of PM 2.5 -induced respiratory diseases.

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“…For example, using both nonselective and subunit-selective ABPs, Kammerl et al observed a reduction in both immunoproteasome activity and MHC class I antigen presentation in response to cigarette smoke. As immunoproteasome activity is a ratelimiting step for MHC class I antigen presentation, the authors speculated that cigarette smoke-impaired immunoproteasome function reduces MHC I-driven immune responses, making smokers more susceptible to viral lung infections [64]. ABP experiments have also suggested a role for the proteasome in epithelialmesenchymal transition (EMT), an important developmental process that is also associated with metastasis [65].…”

Section: Profiling Proteasome Activity Across Different Conditions Ormentioning

confidence: 99%

Activity‐based probes for the multicatalytic proteasome

Hewings¹,

Flygare²,

Wertz³

et al. 2017

The FEBS Journal

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Proteasomes are multisubunit protease complexes responsible for degrading most intracellular proteins. In addition to removing damaged proteins, they regulate many important cellular processes through the controlled degradation of transcription factors, cell cycle regulators, and enzymes. Eukaryotic proteasomes have three catalytic subunits, β1, β2, and β5, that each has different substrate specificities. Additionally, although we know that diverse cell types express proteasome variants with distinct activity and specificity profiles, the functions of these different pools of proteasomes are not fully understood. Covalent inhibitors of the protease activity of the proteasome have been developed as drugs for hematological malignancies and are currently under investigation for other diseases. Therefore, there is a need for tools that allow direct monitoring of proteasome activity in live cells and tissues. Activity‐based probes have proven valuable for biochemical and cell biological studies of the role of individual proteasome subunits, and for evaluating the efficacy and selectivity of proteasome inhibitors. These probes react covalently with the protease active sites, and contain a reporter tag to identify the probe‐labeled proteasome subunits. This review will describe the development of broad‐spectrum and subunit‐specific proteasome activity‐based probes, and discuss how these probes have contributed to our understanding of proteasome biology, and to the development of proteasome inhibitors.

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Impairment of Immunoproteasome Function by Cigarette Smoke and in Chronic Obstructive Pulmonary Disease

Cited by 43 publications

References 52 publications

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Therapeutic effects of stemonine on particulate matter 2.5‑induced chronic obstructive pulmonary disease in mice

Activity‐based probes for the multicatalytic proteasome

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