Mechanisms involved in the metabolic regulation of macrophages by the HIF-1alpha transcription factor

Author(s)

Gustavo Gastão Davanzo

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2022-02-18

Examining board members

Pedro Manoel Mendes de Moraes Vieira; Alicia Juliana Kowaltowski; Marcelo Alves Mori; Marcelo Torres Bozza; José Carlos Alves Filho

• Advisor: Pedro Manoel Mendes de Moraes Vieira

Abstract

Macrophages are cells highly plastic, adaptable, and multifunctional. The cellular metabolism of macrophages is finely regulated according to the energetic and metabolic requirements required to perform their functions. Pro-inflammatory stimuli, such as the presence of gram-negative bacteria, viruses (such as SARS-CoV-2) or free fatty acids (FFA - as found in high concentrations in obese individuals) induce a glycolytic metabolism. This process associated with reduced ATP production by the mitochondria and production of pro-inflammatory cytokines. The hypoxia-induced factor 1 alpha subunit (HIF-1?) has been shown to be an important regulator of the proinflammatory profile and metabolic adaptation of macrophages. The aim of this stuy is to determine the role of the transcription factor HIF-1? in the polarization and metabolic adaptation of macrophages against different inflammatory stimuli. We observed that murine macrophages stimulated with LPS and IFN-? reduce mitochondrial respiration and expression of components of the electron transport chain (ETC). We demonstrate that the deletion of HIF-1? in myeloid cells is sufficient to restore mitochondrial respiration and ETC expression in a mechanism dependent on transcriptional control of the enzymes aconitate decarboxylase 1 (responsible for converting aconitate into itaconate) and nitric oxide synthase 2 (responsible by the production of nitric oxide). We also demonstrate that monocytes infected with SARS-CoV-2 have high production of mitochondrial reactive oxygen species (mtROS), which leads to activation of HIF-1? and subsequent glycolysis. We demonstrate that the excessive production of cytokines by monocytes leads to an impaired proliferation and production of IFN-? by Th1 lymphocytes. We also observed that in models of low-grade inflammation, such as diet-induced obesity, FFAs induce activation of the HIF-1? pathway, leading to mitochondrial fission and the production of pro-inflammatory cytokines in a mechanism dependent of BCL2 Interacting Protein 3 (BNIP3). Together, our data show several inflammatory stimuli that induce the activation of HIF-1? and its target genes, which control mitochondrial morphology and activity via metabolic adaptation and the subsequent inflammatory profile (AU)

• FAPESP's process: 16/18031-8 - HIF-1 alpha in metabolic and functional control of adipose tissue resident macrophages in diabetes induced by obesity
• Grantee: Gustavo Gastão Davanzo
• Support Opportunities: Scholarships in Brazil - Doctorate