Caspase-1 but Not Caspase-11 Is Required for NLRC4-Mediated Pyroptosis and Restriction of Infection by Flagellated Legionella Species in Mouse Macrophages and In Vivo

Autor(es)

Cerqueira, Daiane M. ^[1] ; Pereira, Marcelo S. F. ^[1] ; Silva, Alexandre L. N. ^[1] ; Cunha, Larissa D. ^[1] ; Zamboni, Dario S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Cell Biol, BR-14049900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF IMMUNOLOGY; v. 195, n. 5, p. 2303-2311, SEP 1 2015.
• Citações Web of Science: 32

Resumo

Gram-negative bacteria from the Legionella genus are intracellular pathogens that cause a severe form of pneumonia called Legionnaires' disease. The bacteria replicate intracellularly in macrophages, and the restriction of bacterial replication by these cells is critical for host resistance. The activation of the NAIP5/NLRC4 inflammasome, which is readily triggered in response to bacterial flagellin, is essential for the restriction of bacterial replication in murine macrophages. Once activated, this inflammasome induces pore formation and pyroptosis and facilitates the restriction of bacterial replication in macrophages. Because investigations related to the NLRC4-mediated restriction of Legionella replication were performed using mice double deficient for caspase-1 and caspase-11, we assessed the participation of caspase-1 and caspase-11 in the functions of the NLRC4 inflammasome and the restriction of Legionella replication in macrophages and in vivo. By using several species of Legionella and mice singly deficient for caspase-1 or caspase-11, we demonstrated that caspase-1 but not caspase-11 was required for pore formation, pyroptosis, and restriction of Legionella replication in macrophages and in vivo. By generating F-1 mice in a mixed 129 x C57BL/6 background deficient (129 x Casp-11(-/-)) or sufficient (129 x C57BL/6) for caspase-11 expression, we found that caspase-11 was dispensable for the restriction of Legionella pneumophila replication in macrophages and in vivo. Thus, although caspase-11 participates in flagellin-independent noncanonical activation of the NLRP3 inflammasome, it is dispensable for the activities of the NLRC4 inflammasome. In contrast, functional caspase-1 is necessary and sufficient to trigger flagellin/NLRC4-mediated restriction of Legionella spp. infection in macrophages and in vivo. (AU)

• Processo FAPESP: 12/14456-3 - Subversão das funções do inflamassoma por Coxiella burnetii
• Beneficiário: Larissa Dias da Cunha
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 11/22617-4 - Determinação dos mecanismos funcionais que operam na via de sinalização flagelina-NLRC4-dependente/caspase-1-independente no controle da infecção por L. pneumophila e determinação dos mecanismos que operam de maneira flagelina-independente
• Beneficiário: Marcelo de Souza Fernandes Pereira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• 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: 14/04684-4 - O inflamassoma na resposta contra patógenos intracelulares e os mecanismos microbianos relacionados à evasão
• Beneficiário: Dario Simões Zamboni
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/15932-3 - O papel de NLRC4 e ASC no reconhecimento e controle da infecção por Leishmania (L.) amazonensis.
• Beneficiário: Alexandre Luiz Neves Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/16941-6 - Regulação temporal e transcricional dos inflamassomas no reconhecimento de Legionella pneumophila por macrófagos
• Beneficiário: Daiane Maria Cerqueira
• Modalidade de apoio: Bolsas no Brasil - Mestrado