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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Ketelut-Carneiro, Natalia [1] ; Silva Souza, Camila Oliveira [1] ; Benevides, Luciana [1] ; Gardinassi, Luiz Gustavo [2] ; Silva, Maria Claudia [1] ; Tavares, Lucas Alves [3] ; Zamboni, Dario Simoes [3] ; Silva, Joao Santana [1, 4]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Analyses Toxicol & Food Sci, Ribeirao Preto, SP - Brazil
[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell Biol, Ribeirao Preto, SP - Brazil
[4] Univ Sao Paulo, Ribeirao Preto Med Sch, FIOCRUZ, Biinst Translat Med Project, Ribeirao Preto, SP - Brazil
Total Affiliations: 4
Document type: Journal article
Source: PLOS PATHOGENS; v. 15, n. 8 AUG 2019.
Web of Science Citations: 1
Abstract

The granulomatous lesion resulting from infection with the fungus Paracoccidioides brasiliensis is characterized by a compact aggregate of mature cells, surrounded by a fibroblastand 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 alpha and IL-1 beta. In this study, we addressed the mechanisms underlying IL-1 alpha 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-beta production, because its inhibition reduced procaspase11 levels. Curiously, caspase-11 deficiency did not impair IL-1 beta production, however caspase-11 was required for a rapid pore-mediated cell lysis. The plasma membrane rupture facilitated the release of IL-1 alpha, which was necessary to induce NO production and restrict fungal replication. Furthermore, P. brasiliensis-infected macrophages required IL-1 alpha to produce optimal levels of IL-6, a major component of Th17 lymphocyte differentiation. Indeed, IL-1 alpha 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 alpha 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 alpha production by infected macrophages in vitro, endorsing a critical amplification loop of the inflammatory response. Therefore, our data suggest that the IFN-beta/caspase-11/IL-1 alpha pathway shapes a protective antifungal Th17 immunity, revealing a molecular mechanism underlying the cross-talk between innate and adaptive immunity. (AU)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 13/21295-9 - Role of canonical and non-canonical inflammasome in modulating the innate immune response during infection with Paracoccidioides brasiliensis
Grantee:Natália Ketelut Carneiro
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 12/14524-9 - Modulation of T lymphocytes differentiation in infections by Protozoa, Fungi and Bacteria
Grantee:João Santana da Silva
Support Opportunities: Research Projects - Thematic Grants