The Major Chromoblastomycosis Etiologic Agent Fonsecaea pedrosoi Activates the NLRP3 Inflammasome

Abstract

<i>Fonsecaea pedrosoi</i> is the main etiologic agent of chromoblastomycosis (CBM), one of the most prevalent subcutaneous mycosis in tropical and subtropical countries. CBM is a poorly characterized chronic infection that commonly starts after transcutaneous inoculation of conidia and saprophytic hyphae of <i>F. pedrosoi</i>. Recently, we have shown that unlike conidia, hyphae and muriform cells (the parasitic morphotype) of <i>F. pedrosoi</i> promotes an intense inflammatory response pattern <i>in vivo</i>, which comprises the production of an inflammasome-derived cytokine, IL-1β. Nonetheless, the mechanisms underlying IL-1β production and maturation upon <i>F. pedrosoi</i> infection and its functional output in the course of CBM remains unknown. We show here that <i>F. pedrosoi</i> hyphae, differently from conidia, induce IL-1β secretion in both bone marrow-derived dendritic cells and macrophages. Using inhibitors and knockout cells, we demonstrated that the mechanisms underlying IL-1β production by hyphae-infected macrophages were dependent on dectin-1, -2, and -3 receptors and the Syk-NF-kB signaling pathway. Furthermore, <i>F. pedrosoi</i> promoted a NLRP3-dependent inflammasome activation, which required potassium efflux, reactive oxygen species production, phagolysosomal acidification, and cathepsin B release as triggers. IL-1β processing and release was mediated primarily by caspase-1 and, to a lesser extent, by caspase-8-dependent cleavage. Finally, we showed using a murine CBM model that <i>F. pedrosoi</i> elicits a NLRP3-regulated IL-1β and interleukin-18 release <i>in vivo</i>, but without NLRP3 inflammasome activation interfering in the course of the experimental infection.