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Caspase-11-dependent IL-1α release boosts Th17 immunity against Paracoccidioides brasiliensis

Natália Ketelut-Carneiro¹, Camila Oliveira Silva Souza¹, Luciana Benevides¹

¹Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.

|August 20, 2019

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.

Insights

The IFN-β/caspase-11/IL-1α pathway is crucial for host resistance against Paracoccidioides brasiliensis infection. This pathway promotes Th17 immunity by enhancing IL-1α secretion and reprogramming Th17 lymphocytes, crucial for controlling fungal replication.

Area of Science:

Immunology
Mycology
Cell Biology

Background:

Granuloma formation in response to Paracoccidioides brasiliensis infection involves inflammatory signaling, particularly from the interleukin-1 (IL-1) family.
IL-1α and IL-1β are key members of the IL-1 family, but their specific roles in antifungal immunity require further elucidation.

Purpose of the Study:

To investigate the mechanisms of IL-1α secretion during P. brasiliensis infection.
To determine the functional role of IL-1α in host resistance against this fungal pathogen.
To elucidate the interplay between IL-1α and Th17 cell-mediated immunity.

Main Methods:

Macrophage infection models with P. brasiliensis.
Analysis of caspase-11 expression and its dependence on IFN-β.
Assessment of IL-1α release via pore-mediated cell lysis.
Evaluation of NO production and fungal replication.
Investigation of IL-1α's role in IL-6 production and Th17 lymphocyte differentiation.
Transcriptional profiling of Th17 cells.
In vivo studies using infected mice to assess immune cell infiltration and fungal load.

Main Results:

P. brasiliensis infection triggers caspase-11 expression in macrophages, dependent on IFN-β.
Caspase-11 facilitates rapid pore-mediated cell lysis, leading to IL-1α release.
IL-1α is essential for inducing nitric oxide (NO) production and restricting fungal growth.
IL-1α promotes optimal IL-6 production by macrophages, driving Th17 cell differentiation.
IL-1α deficiency reduces Th17 cells and neutrophil infiltration in infected lungs.
IL-1α directly reprograms Th17 lymphocytes, enhancing their proliferation and IL-17 production.
IL-17 amplifies IL-1α production by macrophages, creating a positive feedback loop.

Conclusions:

The IFN-β/caspase-11/IL-1α pathway is critical for protective antifungal immunity against P. brasiliensis.
IL-1α plays a central role in bridging innate (macrophages) and adaptive (Th17 cells) immunity.
This pathway enhances Th17 responses, leading to increased IL-17 production and effective fungal control.

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