Activation of immune cell proteasomes in peripheral blood of smokers and COPD patients: implications for therapy

Abstract

Immune cells contain a specialised type of proteasome, i.e. the immunoproteasome, which is required for intracellular protein degradation. Immunoproteasomes are key regulators of immune cell differentiation, inflammatory activation and autoimmunity. Immunoproteasome function in peripheral immune cells might be altered by smoking and in COPD thereby affecting immune cell responses.We here analysed the expression and activity of proteasome complexes in peripheral blood mononuclear cells (PBMC) isolated from healthy male young smokers as well as from patients with severe COPD and compared them to matching controls. Proteasome expression was upregulated in COPD patients as assessed by RT-qPCR and mass spectrometry-based proteomics analysis. Proteasome activity was quantified using activity-based probes and native gel analysis. We observed distinct activation of immunoproteasomes in the peripheral blood cells of young male smokers and severely ill COPD patients. Native gel analysis and linear regression modeling confirmed robust activation and elevated assembly of 20S proteasomes, which correlated significantly with reduced lung function parameters in COPD patients. The immunoproteasome was distinctly activated in COPD patients upon inflammatory cytokine stimulation of PBMCs in vitro. Inhibition of the immunoproteasome reduced proinflammatory cytokine expression in COPD-derived blood immune cells.Given the crucial role of chronic inflammatory signalling and the emerging involvement of autoimmune responses in COPD, therapeutic targeting of the immunoproteasome might represent a novel therapeutic concept for COPD.

In-Depth Serum Proteomics by DIA-MS with In Silico Spectral Libraries Reveals Dynamics during the Active Phase of Systemic Juvenile Idiopathic Arthritis

“… 47 − 49 In addition, Ilona Kammerl et al found the activation of immunoproteasomes from peripheral blood mononuclear cells (PBMCs) of patients with severe COPD. 50 Furthermore, because of the activation of immunoproteasomes in PBMCs stimulated by proinflammatory cytokines and because of immunoproteasome inhibition, experimental studies demonstrated cytokine suppression; they suggested that therapeutic targeting of the immunoproteasome may be a novel concept for COPD treatment. Indeed, immunoproteasome inhibitors have been clinically tested in the treatment of autoimmune polymyositis and lupus nephritis ( ) 51 , 52 and are expected to be applied in the treatment of various immune diseases in the clinical setting.…”

“…Recently, the specific inhibition of immunoproteasomes has been shown to suppress the secretion of proinflammatory cytokines (IL-1b, IL-6, IFNγ, TNFα) and activate the expression of IL-10, providing insight into the function of the immunoproteasome in autoimmunity. − In addition, Ilona Kammerl et al found the activation of immunoproteasomes from peripheral blood mononuclear cells (PBMCs) of patients with severe COPD . Furthermore, because of the activation of immunoproteasomes in PBMCs stimulated by proinflammatory cytokines and because of immunoproteasome inhibition, experimental studies demonstrated cytokine suppression; they suggested that therapeutic targeting of the immunoproteasome may be a novel concept for COPD treatment.…”

On the Role of the Immunoproteasome in Protein Homeostasis

“…The involvement of the immunoproteasome in antigen processing influences the pathogen-induced cytotoxic T lymphocyte (CTL) responses, pathogen clearance, and shapes the CTL repertoire [5][6][7][8][9][10]. Apart from MHC-I antigen processing, immunoproteasomes are involved in T cell expansion [7,11,12], T helper cell differentiation [13,14], macrophage polarisation [15,16], in protection from immunopathological damage in the brain [17,18], lung-associated diseases [19][20][21][22], neurodegenerative diseases [23][24][25][26][27][28][29][30][31], and inflammatory diseases [14,[32][33][34][35][36][37][38][39] (summarized in [40]). A specific role of the immunoproteasome in NF-κB activation has remained controversial [41][42][43][44][45].…”

Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study

“…Activation of the immunoproteasome has been reported as a pathomechanistic feature of autoimmune disorders with elevated expression of immunoproteasome subunits in circulating lymphocytes of patients with Sjögren’s Syndrome, myositis, and nephropathies [ 21 , 22 , 23 , 24 ]. Similarly, we recently observed that immunoproteasome activity is activated in peripheral blood mononuclear cells (PBMCs) of patients with severe chronic obstructive pulmonary diseases (COPD), a major tobacco smoke related lung disease [ 25 ]. In contrast, proteasome and immunoproteasome function were inhibited in lungs of patients with severe COPD [ 26 , 27 ] and by exposure to cigarette smoke in vitro and in vivo [ 26 , 28 , 29 , 30 ].…”