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Interferon‐γ regulates cathepsin G activity in microglia‐derived lysosomes and controls the proteolytic processing of myelin basic protein in vitro
Author(s) -
Burster Timo,
Beck Alexander,
Poeschel Simone,
Øren Anita,
Baechle Daniel,
Reich Michael,
Roetzschke Olaf,
Falk Kirsten,
Boehm Bernhard O.,
Youssef Sawsan,
Kalbacher Hubert,
Overkleeft Herman,
Tolosa Eva,
Driessen Christoph
Publication year - 2007
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2007.02540.x
Subject(s) - microglia , proteases , myelin basic protein , cathepsin s , biology , cathepsin , cathepsin d , cathepsin b , cathepsin g , microbiology and biotechnology , cysteine protease , myelin , biochemistry , immunology , inflammation , central nervous system , enzyme , neuroscience
Summary 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‐γ 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.