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

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 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 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 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. Author summary: Buruli ulcer, caused by Mycobacterium ulcerans, is an emerging chronic disease of the skin, characterized by massive skin ulceration. Mycolactone, an exotoxin produced by M. ulcerans is the sole identified virulence factor, but its functions are still unclear. By interfering Sec61 translocon, mycolactone inhibits 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. In this study, we analyzed the activation of inflammasomes in infected macrophages using wild-type and toxin-negative strains of M. ulcerans subsp. shinshuense, and found that mycolactone inhibited IL-1β secretion, but not IL-18, resulting in the exclusive induction of IL-18 by the bacterial infection. 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. Inflammasome activation accompanied by caspase-1 activation in cases of Buruli ulcer appears to be triggered in a manner largely independent of mycolactone. Using a mouse model of Buruli ulcer, we further demonstrated that IL-18 attenuates the progression of Buruli ulcer by controlling accumulation of neutrophils in the infected skin lesions. On the other hand, IL-1β controls bacterial multiplication in the skin. Our results shed light on the etiology of Buruli ulcer and provide insight into the relationship between the activation of inflammasomes and functions of cytokines. [ABSTRACT FROM AUTHOR]