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Published on: July 16, 2019
Interferon-gamma regulates cathepsin G activity in microglia-derived lysosomes and controls the proteolytic
Timo Burster1, Alexander Beck, Simone Poeschel
1Department of Medicine II, University of Tübingen, Germany. tburster@stanford.edu
Abstract:
The serine protease cathepsin (Cat) G dominates the proteolytic processing of the multiple sclerosis (MS)-associated autoantigen myelin basic protein (MBP) in lysosomes from primary human B cells and dendritic cells. This is in contrast to B-lymphoblastoid cell lines, where the asparagine endopeptidase (AEP) is responsible for this task. We have analysed microglia-derived lysosomal proteases for their ability to process MBP in vitro. In lysosomes derived from primary murine microglia, CatD, CatS, AEP and CatG were involved in the processing of MBP. Interestingly, when microglia were treated with interferon-gamma to mimic a T helper type 1-biased cytokine milieu in MS, CatG was drastically down-regulated, in contrast to CatS, CatB, CatL, CatD or AEP. This resulted in significantly increased stability of MBP and a selective lack of CatG-derived proteolytic fragments; however, it did not affect the gross pattern of MBP processing. Inhibition of serine proteases eliminated the processing differences between lysosomal extracts from resting microglia compared to interferon-stimulated microglia. Thus, the cytokine environment modulates lysosomal proteases in microglia by a selective down-regulation of CatG, leading to decreased MBP-processing by microglia-derived lysosomal proteases in vitro.
Insights
Multiple sclerosis (MS) research reveals that interferon-gamma down-regulates cathepsin G in microglia, reducing myelin basic protein (MBP) processing. This finding impacts understanding of MS pathogenesis and therapeutic targets.
Area of Science:
- Neuroimmunology
- Protease biochemistry
- Autoimmune disease research
Background:
- The multiple sclerosis (MS)-associated autoantigen myelin basic protein (MBP) is processed by specific proteases in immune cells.
- Cathepsin G (CatG) is a key protease for MBP processing in human B cells and dendritic cells, while asparagine endopeptidase (AEP) acts in B-lymphoblastoid cell lines.
Purpose of the Study:
- To investigate the role of microglia-derived lysosomal proteases in processing MBP.
- To determine how the cytokine environment, mimicking MS conditions, affects these proteases and MBP processing in microglia.
Main Methods:
- Analysis of lysosomal proteases from primary murine microglia.
- In vitro processing assays of MBP using microglial lysosomal extracts.
- Treatment of microglia with interferon-gamma to simulate a T helper type 1 (Th1) cytokine milieu.
- Inhibition of serine proteases to assess their role in MBP processing differences.
Main Results:
- Multiple proteases including CatD, CatS, AEP, and CatG were identified in microglial lysosomes involved in MBP processing.
- Interferon-gamma treatment significantly down-regulated CatG expression in microglia, while other proteases remained unaffected.
- Down-regulation of CatG led to increased MBP stability and a lack of CatG-specific fragments, without altering the overall MBP processing pattern.
- Inhibition of serine proteases abolished the observed processing differences between resting and interferon-gamma-stimulated microglia.
Conclusions:
- The cytokine environment in microglia modulates lysosomal protease activity, specifically down-regulating CatG.
- This selective CatG down-regulation by interferon-gamma reduces microglial processing of MBP in vitro.
- These findings highlight a mechanism by which microglia contribute to antigen presentation in the context of MS.
