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LYSOSOMAL CATHEPSIN RELEASE IS REQUIRED FOR NLRP3-INFLAMMASOME ACTIVATION BY MYCOBACTERIUM TUBERCULOSIS IN INFECTED MACROPHAGES
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Resumo em Inglês
Lysosomal cathepsin B (CTSB) has been proposed to play a role in the induction of
acute inflammation. We hypothesised that the presence of active CTSB in the cytosol
is crucial for NLRP3-inflammasome assembly and, consequently, for mature IL-1β generation
after mycobacterial infection in vitro. Elevated levels of CTSB was observed in
the lungs of mice and rabbits following infection with Mycobacterium tuberculosis (Mtb)
H37Rv as well as in plasma from acute tuberculosis patients. H37Rv-infected murine
bone marrow-derived macrophages (BMDMs) displayed both lysosomal leakage, with
release of CTSB into the cytosol, as well as increased levels of mature IL-1β. These
responses were diminished in BMDM infected with a mutant H37Rv deficient in ESAT-6
expression. Pharmacological inhibition of cathepsin activity with CA074-Me resulted in
a substantial reduction of both mature IL-1β production and caspase-1 activation in
infected macrophages. Moreover, cathepsin inhibition abolished the interaction between
NLRP3 and ASC, measured by immunofluorescence imaging in H37Rv-infected macrophages,
demonstrating a critical role of the enzyme in NLRP3-inflammasome activation.
These observations suggest that during Mtb infection, lysosomal release of activated
CTSB and possibly other cathepsins inhibitable by CA07-Me is critical for the induction
of inflammasome-mediated IL-1β processing by regulating NLRP3-inflammasome
assembly in the cytosol.
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