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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 15, n. 8 AUG 2019.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 13/21295-9 - Papel do inflamassoma canônico e não canônico na modulação da resposta imune inata durante a infecção por Paracoccidioides brasiliensis
• Beneficiário: Natália Ketelut Carneiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 12/14524-9 - Modulação da diferenciação de linfócitos T em infecções por protozoários, fungos e bactérias
• Beneficiário: João Santana da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Temático