Upregulation of Immunoproteasome Subunits

 

Proteasome
 

The proteasome is a multi-catalytic protein complex whose primary function is the degradation of abnormal or foreign proteins. Upon exposure of cells to interferons (IFNs), the β1i/LMP2, β2i/MECL-1, and β5i/LMP7 subunits are induced and incorporated into newly synthesized immunoproteasomes (IP), which are thought to function solely as critical players in the optimization of the CD8⁺ T-cell response. However, the observation that IP are present in several non-immune tissues under normal conditions and/or following pathological events mitigates against the view that its role is limited to MHC class I presentation.

In idiopathic inflammatory myopathies (IIM) infiltration of immune cells into muscle and upregulation of MHC-I expression implies increased antigen presentation and involvement of the proteasome system. (1). One study focuses on  the up-regulation of immunoproteasome subunits in myositis indicates active inflammation with involvement of antigen presenting cells, CD8 T-Cells and IFNγ; in this study the expression of constitutive (PSMB5, -6, -7) and corresponding immunoproteasomal subunits (PSMB8, -9, -10) was analyzed by real-time RT-PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). Protein analysis in muscle biopsies was performed by western blot. Real-time RT-PCR revealed significantly increased expression of immunoproteasomal subunits (PSMB8/-9/-10) in DC, monocytes and CD8+ T-cells in IIM. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed these results and revealed involvement of the antigen processing and presentation pathway. Immunoproteasomes seem to indicate IIM activity and suggest that dominant involvement of antigen processing and presentation may qualify these diseases exemplarily for the evolving therapeutic concepts of immunoproteasome specific inhibition.

 Many studies suggest that the proteasome participates in muscle fiber degradation in various physiological and pathological conditions and may therefore also play an important role in myositis. (2)(3)

 

Immunoproteasome and MHC-I

Importantly, under the influence of the pro-inflammatory cytokine IFNγ, the structure and the catalytic properties of the constitutive proteasome are modified by substitution of the catalytic subunits PSMB5, PSMB6 and PSMB7 with three catalytic immunosubunits proteasome subunit beta type 8-PSMB8, proteasome subunit beta type 9-PSMB9 and proteasome subunit beta type 10-PSMB10 respectively, leading to the formation of the so-called immunoproteasome. This process is considered to strongly influence the production of peptides for antigen presentation by MHC class I as well as the immune response. (4)(5)

Elevated levels of circulating proteasomes as well as autoantibodies against several proteasomal subunits have been detected in patients with autoimmune myositis and other autoimmune disorders. (6)

The proteasome system is activated and contributes to a perpetuating crosstalk between antigen-presenting cells and T-cells via immunoproteasome generated peptides and IFNγ. Assuming altered autoantigen processing as driving mechanism, suppression of the immunoproteasome could be a promising therapeutic concept.

We conclude that the MHC up regulation precedes the inflammatory cytokines and the infiltrating leukocytes, and the MHC up regulation could be caused by these immunoproteasomes.
 

Stress Pathway Activation

The muscle weakness often may precede the infiltration. Some studies suggest the possibility of stress in the endoplasmic reticulum being involved. 

A group of IIM Patients has elevated creatine kinase levels with an array of circulating myositis-specific autoantibodies. Up regulation of major histocompatibility complex (MHC) I molecules in vitro and in vivo is also a characteristic histological finding, and associated with activation of the Endoplasmic Reticulum (ER) stress response. (7)

The muscle is potentially a source of various cytokines, a process mediated here via ER stress pathway activation. These findings suggest that muscle cells may exhibit chemotactic capability, so attracting immune cells. Such myokines release suggests muscle may exert paracrine signals on neighbouring fibers, which could contribute to muscle dysfunction in the absence of immune cells. Skeletal muscle may thus act as a source of cytokines in the IIM. Targeted therapies towards myokine reduction may thus be worthy of further investigation, to further understand muscle dysfunction in IIM. (7)

Data from non-muscle cells indicate that endoplasmic reticulum stress results in altered redox homeostasis capable of causing oxidative damage. In myopathological situations other than IIM, as seen in ageing and sepsis, evidence supports an important role for reactive oxygen species (ROS). Modified ROS generation is associated with mitochondrial dysfunction, depressed force generation and activation of muscle catabolic and autophagy pathways. The authors suggest that ROS-mediated mechanisms are potentially involved in non-immune cell mediated weakness seen in IIM.  This appears a timely strategy, given recent developments in targeted therapies which specifically modify ROS generation. (8)

Article contributed by Dr. JOSE PEREIRA, MD

Footnotes:

1. Ghannam K. Upregulation of Immunoproteasome Subunits in Myositis Indicates Active Inflammation with Involvement of Antigen Presenting Cells, CD8 T-Cells and IFNγ. Published: August 6, 2014 .DOI: 10.1371/journal.pone.010404. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104048.
    
2. Kumamoto T.Proteasome expression in the skeletal muscles of patients with muscular dystrophy. Acta Neuropathol 100: 595–602. doi: 10.1007/s004010000229. http://link.springer.com/article/10.1007%2Fs004010000229
    
3. Mitch WE, Goldberg AL (1996) Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med 335: 1897–1905. doi: 10.1056/nejm199612193352507.http://www.nejm.org/doi/full/10.1056/NEJM199612193352507
    
4. Aki M. Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. J Biochem 115: 257–269. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Aki%5Bauthor%5D%20AND%20Interferon-gamma%20induces%20different%20subunit%20organizations%20and%20functional%20diversity%20of%20proteasomes
    
5. Boes B. Interferon gamma stimulation modulates the proteolytic activity and cleavage site preference of 20S mouse proteasomes. J Exp Med 179: 901–909. doi: 10.1084/jem.179.3.901. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Boes%5Bauthor%5D%20AND%20Interferon%20gamma%20stimulation%20modulates%20the%20proteolytic%20activity%20and%20cleavage%20site%20preference%20of%2020S%20mouse%20proteasomes
    
6. Egerer K. Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases. J Rheumatol 29: 2045–2052. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Egerer%5Bauthor%5D%20AND%20Circulating%20proteasomes%20are%20markers%20of%20cell%20damage%20and%20immunologic%20activity%20in%20autoimmune%20disease
    
7. Lightfoot A. Investigating the Pathogenic Role of ER Stress Pathway Activation in the Idiopathic Inflammatory Myopathies (IIM): Skeletal Muscle Cells As a Source of Cytokines (Myokines). Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/investigating-the-pathogenic-role-of-er-stress-pathway-activation-in-the-idiopathic-inflammatory-myopathies-iim-skeletal-muscle-cells-as-a-source-of-cytokines-myokines/. Accessed January 7, 2016.
    
8. Lightfoot A. In the idiopathic inflammatory myopathies (IIM), do reactive oxygen species (ROS) contribute to muscle weakness?. Ann Rheum Dis 2015;74:11 e63. http://ard.bmj.com/content/early/2015/04/28/annrheumdis-2014-207172.abstract#cited-by

 

 

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