Human monocytes and macrophages differ in their mechanisms of adaptation to hypoxia
Monique Fangradt,M. Hahne,Timo Gaber,C. Strehl,Roman Rauch,Paula Hoff,Max Löhning,Gerd-Rüdiger Burmester,Frank Buttgereit +8 more
TLDR
It is demonstrated that during differentiation of monocytes into macrophages, crucial cellular adaptation mechanisms are decisively changed, apparently as an adaptation to a low oxygen environment.Abstract:
Inflammatory arthritis is a progressive disease with chronic inflammation of joints, which is mainly characterized by the infiltration of immune cells and synovial hyperproliferation. Monocytes migrate towards inflamed areas and differentiate into macrophages. In inflamed tissues, much lower oxygen levels (hypoxia) are present in comparison to the peripheral blood. Hence, a metabolic adaptation process must take place. Other studies suggest that Hypoxia Inducible Factor 1-alpha (HIF-1α) may regulate this process, but the mechanism involved for human monocytes is not yet clear. To address this issue, we analyzed the expression and function of HIF-1α in monocytes and macrophages, but also considered alternative pathways involving nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB). Isolated human CD14+ monocytes were incubated under normoxia and hypoxia conditions with or without phorbol 12-myristate 13-acetate (PMA) stimulation, respectively. Nuclear and cytosolic fractions were prepared in order to detect HIF-1α and NFκB by immunoblot. For the experiments with macrophages, primary human monocytes were differentiated into human monocyte derived macrophages (hMDM) using human macrophage colony-stimulating factor (hM-CSF). The effects of normoxia and hypoxia on gene expression were compared between monocytes and hMDMs using quantitative PCR (quantitative polymerase chain reaction). We demonstrate, using primary human monocytes and hMDM, that the localization of transcription factor HIF-1α during the differentiation process is shifted from the cytosol (in monocytes) into the nucleus (in macrophages), apparently as an adaptation to a low oxygen environment. For this localization change, protein kinase C alpha/beta 1 (PKC-α/β1 ) plays an important role. In monocytes, it is NFκB1, and not HIF-1α, which is of central importance for the expression of hypoxia-adjusted genes. These data demonstrate that during differentiation of monocytes into macrophages, crucial cellular adaptation mechanisms are decisively changed.read more
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Journal ArticleDOI
Mitochondrial complex II regulates a distinct oxygen sensing mechanism in monocytes.
TL;DR: A novel role for mitochondrial respiratory inhibition in induction of the hypoxic transcriptome in monocytes is revealed and it is suggested that inhibition of complex II activates a distinct hypoxia signaling pathway in a cell-type specific manner.
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The Role of Immune Reactivity in Bone Regeneration
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Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2
Tianshi Feng,Xuemei Zhao,Ping Gu,Wah Yang,Cunchuan Wang,Qing-yu Guo,Qi-Fu Long,Qing Liu,Ying Cheng,Jin Li,Cynthia K. Cheung,Donghai Wu,Xinyu Kong,Yong Xu,Dewei Ye,Shuang Hua,Kerry M. Loomes,Aimin Xu,Xiaoyan Hui +18 more
TL;DR: In this article , the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α).
Palmitic Acid Activation of Dendritic Cells: Implications for Type 2 Diabetes
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References
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Guang L. Wang,Gregg L. Semenza +1 more
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Guang L. Wang,Gregg L. Semenza +1 more
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Hypoxia Induces Cyclooxygenase-2 via the NF-κB p65 Transcription Factor in Human Vascular Endothelial Cells
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Journal ArticleDOI
Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha.
M. S. Wiesener,H. Turley,H. Turley,William Allen,William Allen,C. Willam,C. Willam,Kai-Uwe Eckardt,Kai-Uwe Eckardt,K.L. Talks,K.L. Talks,S.M. Wood,S.M. Wood,K.C. Gatter,K.C. Gatter,A.L. Harris,A.L. Harris,Christopher W. Pugh,Christopher W. Pugh,Peter J. Ratcliffe,Peter J. Ratcliffe,P. H. Maxwell,P. H. Maxwell +22 more
TL;DR: Functional studies in a mutant cell line expressing neither HIF-1alpha nor EPAS-1 confirmed that both proteins interact with hypoxically responsive targets, but suggest target specificity with greater EPas-1 transactivation of the VEGF promoter than the LDH-A promoter.
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