It is logical to assume that a major pro-inflammatory mechanism, i.e., the NLRP3 inflammasome would play a prominent role in the pathogenesis of the Inflammatory Bowel Disease (IBD) in humans. However, while both studies of murine models of gut disease and patients provide data that the main cytokine product generated by this inflammasome, IL-1β, does in fact contribute to inflammation in IBD, there is no evidence that IL-1β plays a decisive or prominent role in “ordinary” patients with IBD (Crohn's disease). On the other hand, there are several definable point mutations that result in over-active NLRP3 inflammasome activity and in these cases, the gut inflammation is driven by IL-1β and is treatable by biologic agents that block the effects of this cytokine.

No abstract

No abstract

Microsporum canis is a pathogenic fungus with worldwide distribution that causes tinea capitis in animals and humans. M. canis also causes invasive infection in immunocompromised patients. To defy pathogenic fungal infection, the host innate immune system is the first line of defense. As an important arm of innate immunity, the inflammasomes are intracellular multiprotein complexes that control the activation of caspase-1, which cleaves proinflammatory cytokine pro-interleukin-1␤ (IL-1␤) into its mature form. To determine whether the inflammasome is involved in the host defense against M. canis infection, we challenged human monocytic THP-1 cells and mouse dendritic cells with a clinical strain of M. canis isolated from patients with tinea capitis. We found that M. canis infection triggered rapid secretion of IL-1␤ from both THP-1 cells and mouse dendritic cells. Moreover, by using gene-specific shRNA and competitive inhibitors, we determined that M. canis-induced IL-1␤ secretion was dependent on NLRP3. The pathways proposed for NLRP3 inflammasome activation, namely, cathepsin B activity, K ؉ efflux, and reactive oxygen species production, were all required for the inflammasome activation triggered by M. canis. Meanwhile, Syk, Dectin-1, and Card9 were found to be involved in M. canis-induced IL-1␤ secretion via regulation of pro-IL-1␤ transcription. More importantly, our data revealed that M. canis-induced production of IL-1␤ was dependent on the NLRP3 inflammasome in vivo. Together, this study unveils that the NLRP3 inflammasome exerts a critical role in host innate immune responses against M. canis infection, and our data suggest that diseases that result from M. canis infection might be controlled by regulating the activation of inflammasomes.