%0 Journal Article
%T Caspase-11-dependent IL-1¦Á release boosts Th17 immunity against Paracoccidioides brasiliensis
%A Camila Oliveira Silva Souza
%A Dario Sim£¿es Zamboni
%A Jo£¿o Santana Silva
%A Lucas Alves Tavares
%A Luciana Benevides
%A Luiz Gustavo Gardinassi
%A Maria Cl¨¢udia Silva
%A Nat¨¢lia Ketelut-Carneiro
%J -
%D 2019
%R 10.1371/journal.ppat.1007990
%X The granulomatous lesion resulting from infection with the fungus Paracoccidioides brasiliensis is characterized by a compact aggregate of mature cells, surrounded by a fibroblast- and collagen-rich content. Granuloma formation requires signaling elicited by inflammatory molecules such as members of the interleukin-1 family. Two members of this family have been thoroughly studied, namely IL-1¦Á and IL-1¦Â. In this study, we addressed the mechanisms underlying IL-1¦Á secretion and its functional role on the host resistance to fungal infection. We found that, the expression of caspase-11 triggered by P. brasiliensis infection of macrophages depends on IFN-¦Â production, because its inhibition reduced procaspase-11 levels. Curiously, caspase-11 deficiency did not impair IL-1¦Â production, however caspase-11 was required for a rapid pore-mediated cell lysis. The plasma membrane rupture facilitated the release of IL-1¦Á, which was necessary to induce NO production and restrict fungal replication. Furthermore, P. brasiliensis-infected macrophages required IL-1¦Á to produce optimal levels of IL-6, a major component of Th17 lymphocyte differentiation. Indeed, IL-1¦Á deficiency accounted for a significant reduction of Th17 lymphocytes in lungs of infected mice, correlating with diminished neutrophil infiltration in the lungs. Strikingly, we identified that IL-1¦Á directly reprograms the transcriptional profile of Th17-committed lymphocytes, increasing cellular proliferation, as for boosting IL-17 production by these cells. Beyond neutrophil chemotaxis in vivo, IL-17 also amplified IL-1¦Á production by infected macrophages in vitro, endorsing a critical amplification loop of the inflammatory response. Therefore, our data suggest that the IFN-¦Â/caspase-11/IL-1¦Á pathway shapes a protective antifungal Th17 immunity, revealing a molecular mechanism underlying the cross-talk between innate and adaptive immunity
%K Macrophages
%K Yeast infections
%K Fungal diseases
%K Cell differentiation
%K T cells
%K Fungi
%K Paracoccidioides brasiliensis
%K Cytokines
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007990