IF-1 alpha Stabilization in Flagellin-Stimulated Human Bronchial Cells Impairs Barrier Functio

Autor(es)

Ramirez-Moral, Ivan ^[1] ; Ferreira, Bianca L. ^{[1, 2]} ; Butler, Joe M. ^[1] ; van Weeghel, Michel ^{[3, 4]} ; Otto, Natasja A. ^[1] ; de Vos, Alex F. ^[1] ; Yu, Xiao ^[5] ; de Jong, Menno D. ^[5] ; Houtkooper, Riekelt H. ^[3] ; van der Poll, Tom ^{[1, 6]}

Afiliação do(s) autor(es)

^[1] Univ Amsterdam, Ctr Expt & Mol Med, Amsterdam Infect & Immun Inst, Amsterdam UMC, NL-1105 AZ Amsterdam - Netherlands

^[2] Univ Fed Sao Paulo, Div Infect Dis, Dept Med, Escola Paulista Med, BR-04023062 Sao Paulo - Brazil

^[3] Univ Amsterdam, Lab Genet Metab Dis, Amsterdam Gastroenterol Endocrinol & Metab, Amsterdam Cardiovasc Sci, Amsterdam UMC, NL-1105 AZ Amsterdam - Netherlands

^[4] Univ Amsterdam, Core Facil Metabol, Amsterdam UMC, NL-1105 AZ Amsterdam - Netherlands

^[5] Univ Amsterdam, Dept Med Microbiol, Amsterdam UMC, NL-1105 AZ Amsterdam - Netherlands

^[6] Univ Amsterdam, Div Infect Dis, Amsterdam UMC, NL-1105 AZ Amsterdam - Netherlands

• Tipo de documento: Artigo Científico
• Fonte: ELL; v. 11, n. 3 FEB 2022.
• Citações Web of Science: 0

Resumo

The respiratory epithelium provides a first line of defense against pathogens. Hypoxia-inducible factor (HIF)1 alpha is a transcription factor which is stabilized in hypoxic conditions through the inhibition of prolyl-hydroxylase (PHD)2, the enzyme that marks HIF1 alpha for degradation. Here, we studied the impact of HIF1 alpha stabilization on the response of primary human bronchial epithelial (HBE) cells to the bacterial component, flagellin. The treatment of flagellin-stimulated HBE cells with the PHD2 inhibitor IOX2 resulted in strongly increased HIF1 alpha expression. IOX2 enhanced the flagellin-induced expression of the genes encoding the enzymes involved in glycolysis, which was associated with the intracellular accumulation of pyruvate. An untargeted pathway analysis of RNA sequencing data demonstrated the strong inhibitory effects of IOX2 toward key innate immune pathways related to cytokine and mitogen-activated kinase signaling cascades in flagellin-stimulated HBE cells. Likewise, the cell-cell junction organization pathway was amongst the top pathways downregulated by IOX2 in flagellin-stimulated HBE cells, which included the genes encoding claudins and cadherins. This IOX2 effect was corroborated by an impaired barrier function, as measured by dextran permeability. These results provide a first insight into the effects associated with HIF1 alpha stabilization in the respiratory epithelium, suggesting that HIF1 alpha impacts properties that are key to maintaining homeostasis upon stimulation with a relevant bacterial agonist. (AU)

• Processo FAPESP: 19/02224-0 - Metabolismo de células epiteliais e células imunes das vias aéreas na homeostase e inflamação
• Beneficiário: Bianca Rodrigues Lima Ferreira
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado