Caspase-11-dependent IL-1α release boosts Th17 immunity against Paracoccidioides brasiliensis
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2019
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The granulomatous lesion resulting from infection with the fungus Paracoccidioides brasi liensis 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 mecha nisms 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 cas pase-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 pro duce 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 lym phocytes, 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
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KETELUT-CARNEIRO, Natália et al. Caspase-11-dependent IL-1α release boosts Th17 immunity against Paracoccidioides brasiliensis. PLoS Pathogens, San Francisco, v. 15, n. 8, e1007990, 2019. DOI: 10.1371/journal.ppat.1007990. Disponível em: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007990. Acesso em: 29 jan. 2025.