Inflammasome-triggered IL-18 controls skin inflammation in the progression of Buruli ulcer
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Date
2023
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PLOS Pathogens
Abstract
Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence
factor so far, but the functions of this toxin and the mechanisms of disease progression
remain unclear. By interfering with the Sec61 translocon, mycolactone inhibits the Sec61-dependent
co-translational translocation of newly synthesized proteins, such as induced cytokines and
immune cell receptors into the endoplasmic reticulum. However, in regard to IL-1β, which is
Secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1β secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1β, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the
Inflammasome activation is triggered in a manner independent of mycolactone. Intriguingly,
mycolactone suppressed the expression of proIL-1β as well as TNF-α at the transcriptional
level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional
inhibitory effect on proIL-1β expression. Remarkably, constitutively produced IL-18 was
cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans experienced exacerbated skin inflammation during the course of disease progression. On the other
On the other hand, IL-1β controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of
Buruli ulcer.
Description
Research Article
Keywords
Buruli ulcer, skin inflammation, progression