title: Lack of the Transcription Factor Hypoxia-Inducible Factor 1α (HIF-1α) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas.
abstract: 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 1α (HIF-1α) under the Cre-lox system regulated by the lysozyme M gene promoter was used to determine the relevance of HIF-1α in the caseation of granulomas. The genetic ablation of HIF-1α 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-1α in a necrotizing mouse model. Our results show that interfering with macrophage adaptation to hypoxia, such as through HIF-1α inactivation, accelerates granuloma necrosis.
authors.affiliation: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Marcos S
authors.initials: MS
authors.lastname: Cardoso
authors.affiliation: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Tânia M
authors.initials: TM
authors.lastname: Silva
authors.affiliation: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Resende
authors.affiliation: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal rappelb@ibmc.up.pt mborges@ff.up.pt.
authors.forename: Rui
authors.initials: R
authors.lastname: Appelberg
authors.affiliation: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal UCIBIO/REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia da Universidade do Porto, Porto, Portugal rappelb@ibmc.up.pt mborges@ff.up.pt.
authors.forename: Margarida
authors.identifier: http://orcid.org/0000-0001-6035-4095
authors.initials: M
authors.lastname: Borges
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006099:Granuloma / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000378:metabolism / Q000473:pathology*; D009162:Mycobacterium avium; D009336:Necrosis / Q000378:metabolism* / Q000382:microbiology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit