Lack of the Transcription Factor Hypoxia-Inducible Factor 1 alpha (HIF-1 alpha) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas

• Tipo: Artigo em Revista Científica Internacional
• Data: 2015

Autores

Marcos S Cardoso (Autor) Outra; Tania M Silva (Autor) Outra; Mariana Resende (Autor) Outra; Rui Appelberg (Autor) Outra; Margarida Borges (Autor) FFUP

Revista

Título: Infection and Immunity

Vol. 83

Páginas: 3534-3544

ISSN: 0019-9567

Editora: American Society for Microbiology

Indexação

ISI Web of Knowledge - 12 Citações

Scopus - 20 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: P-00G-G24

DOI: 10.1128/iai.00144-15

Abstract (EN): The establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely, infected macrophages. The granuloma's main function is to constrain and prevent dissemination of the mycobacteria while focusing the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis, thereby leading to their caseation. Macrophages are the most abundant cells present in the granuloma and are known to adapt under hypoxic conditions in order to avoid cell death. Our laboratory has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis, using C57BL/6 mice infected intravenously with a low dose of a highly virulent strain of Mycobacterium avium. In this work, a mouse strain deleted of the hypoxia inducible factor 1 alpha (HIF-1 alpha) under the Cre-lox system regulated by the lysozyme M gene promoter was used to determine the relevance of HIF-1 alpha in the caseation of granulomas. The genetic ablation of HIF-1 alpha in the myeloid lineage causes the earlier emergence of granuloma necrosis and clearly induces an impairment of the resistance against M. avium infection coincident with the emergence of necrosis. The data provide evidence that granulomas become hypoxic before undergoing necrosis through the analysis of vascularization and quantification of HIF-1 alpha in a necrotizing mouse model. Our results show that interfering with macrophage adaptation to hypoxia, such as through HIF-1 alpha inactivation, accelerates granuloma necrosis.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11