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- Title
Caspase-11-dependent IL-1α release boosts Th17 immunity against Paracoccidioides brasiliensis.
- Authors
Ketelut-Carneiro, Natália; Souza, Camila Oliveira Silva; Benevides, Luciana; Gardinassi, Luiz Gustavo; Silva, Maria Cláudia; Tavares, Lucas Alves; Zamboni, Dario Simões; Silva, João Santana
- Abstract
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-1α and IL-1β. In this study, we addressed the mechanisms underlying IL-1α 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-β production, because its inhibition reduced procaspase-11 levels. Curiously, caspase-11 deficiency did not impair IL-1β production, however caspase-11 was required for a rapid pore-mediated cell lysis. The plasma membrane rupture facilitated the release of IL-1α, which was necessary to induce NO production and restrict fungal replication. Furthermore, P. brasiliensis-infected macrophages required IL-1α to produce optimal levels of IL-6, a major component of Th17 lymphocyte differentiation. Indeed, IL-1α 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-1α 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-1α production by infected macrophages in vitro, endorsing a critical amplification loop of the inflammatory response. Therefore, our data suggest that the IFN-β/caspase-11/IL-1α pathway shapes a protective antifungal Th17 immunity, revealing a molecular mechanism underlying the cross-talk between innate and adaptive immunity.
- Subjects
PARACOCCIDIOIDES brasiliensis; CHEMOTAXIS; IMMUNITY; NATURAL immunity; LEUCOCYTES; DEVELOPMENTAL biology
- Publication
PLoS Pathogens, 2019, Vol 15, Issue 8, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1007990