Inflammasome-triggered IL-18 controls skin inflammation in the progression of Buruli ulcer

DOI DOI DOI Web Site PubMed 57 References Open Access

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<jats:p>Buruli ulcer is an emerging chronic infectious skin disease caused by <jats:italic>Mycobacterium ulcerans</jats:italic>. 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 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 <jats:italic>M</jats:italic>. <jats:italic>ulcerans</jats:italic> subsp. <jats:italic>shinshuense</jats:italic>, despite the activation of caspase-1 through the inflammasome activation 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 <jats:italic>M</jats:italic>. <jats:italic>ulcerans</jats:italic> subsp. <jats:italic>shinshuense</jats:italic> 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 <jats:italic>M</jats:italic>. <jats:italic>ulcerans</jats:italic> exhibited exacerbated skin inflammation during the course of disease progression. 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.</jats:p>

Journal

  • PLOS Pathogens

    PLOS Pathogens 19 (11), e1011747-, 2023-11-01

    Public Library of Science (PLoS)

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