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

Abstract

Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression.

Profiling Proteasome Activities in Peripheral Blood – A Novel Biomarker Approach

“…It also changes with age, as almost all catalytic activities of the proteasome were activated in aged women while maintained in ageing men. Moreover, we showed distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, asthma, cardiovascular or chronic obstructive pulmonary diseases [38]. In accordance with these data, a recent study has also suggested profiling the activity of PBMC's immunoproteasome as a sensitive biomarker for the disease activity of Systemic juvenile idiopathic arthritis (sJIA), enabling the detailed evaluation of response to treatment.…”

“…This led us to suggest that proteasome activity profiling in PBMCs might serve as a biomarker for inflammation and pathology severity. We corroborated this concept by examining the proteasome activity profile of PBMCs in the large population-based KORA F4 cohort of 924 subjects [38]. In this study, we demonstrated for the first time, that the proteasome activity profile in PBMCs has a strong sex dimorphism with significantly lower immunoproteasome activity in women.…”

“…ABP analysis also offers the potential of flow cytometry-based quantification, which can be combined with single subunit expression analysis for defined immune cell populations. In light of the unexpected sex-related regulation of immunoproteasome activity, we urgently need large study cohorts to stratify for sex but also age and BMI [38]. Understanding the role of the distinct immunoproteasome and intermediate proteasome complexes for immune cell function will also pave the way for the application of site-specific immunoproteasome inhibitors to specifically target unwanted immune cell functions, as exemplarily shown for the immunoproteasome specific inhibitor ONX0914 that is currently tested in clinical phase II for Lupus Erythematodes (www.clinicaltrials.gov) [52].…”

“…Similar ABPs-based methods are also used to assess the proteasome activity in cell-based imaging procedures [45,50,51]. This profiling methods thereby the side-byside quantification of the different active sites enabling the detection of intermediate proteasome complexes [38].…”

“…These data suggest that such complexes can be forced to form and that they are stable [17,25,[32][33][34][35][36][37]. Of note, recent data that quantified all proteasome catalytic subunits in human peripheral immune cells using Activity-based Probes (ABPs) also suggested a stoichiometry of intermediate proteasomes other than only single and double immunoproteasomes which conflicts with the reported rules of cooperative incorporation [38,39]. To solve this ambiguity, it is crucial to develop new analytic methods for profiling the activity of each of the proteasome's six distinct catalytic active sites.…”