Hypoxia-inducible factor controls immunoregulatory properties of myeloid cells in mouse cardiac allografts - an experimental study

Keränen, Mikko; Raissadati, Alireza; Nykänen, Antti; Dashkevich, Alexey; Tuuminen, Raimo; Krebs, R.; Johnson, Randall S.; Syrjälä, S.; Lemström, Karl

doi:10.1111/tri.13310

Cited by 8 publications

(4 citation statements)

References 33 publications

(46 reference statements)

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“…The presence of chemokines or chemokine-producing immune cells can however increase the expression of IDO1 under hypoxia (54, 56). Other studies have also reported the upregulation of IDO1 expression upon hypoxic exposure or HIF1α stabilization in neural and immune cells (57–59). Taken together, these studies indicate that the regulation of IDO1 under hypoxic conditions is highly cell type specific and also depends upon microenvironmental factors such as immune cell infiltration.…”

Section: Discussionmentioning

confidence: 87%

Hypoxia Inducible Factor 1α Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma

et al. 2019

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Abnormal circulation in solid tumors results in hypoxia, which modulates both tumor intrinsic malignant properties as well as anti-tumor immune responses. Given the importance of hypoxia in glioblastoma (GBM) biology and particularly in shaping anti-tumor immunity, we analyzed which immunomodulatory genes are differentially regulated in response to hypoxia in GBM cells. Gene expression analyses identified the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2) as the second most downregulated gene in GBM cells cultured under hypoxic conditions. TDO2 catalyses the oxidation of tryptophan to N-formyl kynurenine, which is the first and rate-limiting step of Trp degradation along the kynurenine pathway (KP). In multiple GBM cell lines hypoxia reduced TDO2 expression both at mRNA and protein levels. The downregulation of TDO2 through hypoxia was reversible as re-oxygenation rescued TDO2 expression. Computational modeling of tryptophan metabolism predicted reduced flux through the KP and lower intracellular concentrations of kynurenine and its downstream metabolite 3-hydroxyanthranilic acid under hypoxia. Metabolic measurements confirmed the predicted changes, thus demonstrating the ability of the mathematical model to infer intracellular tryptophan metabolite concentrations. Moreover, we identified hypoxia inducible factor 1α (HIF1α) to regulate TDO2 expression under hypoxic conditions, as the HIF1α-stabilizing agents dimethyloxalylglycine (DMOG) and cobalt chloride reduced TDO2 expression. Knockdown of HIF1α restored the expression of TDO2 upon cobalt chloride treatment, confirming that HIF1α controls TDO2 expression. To investigate the immunoregulatory effects of this novel mechanism of TDO2 regulation, we co-cultured isolated T cells with TDO2-expressing GBM cells under normoxic and hypoxic conditions. Under normoxia TDO2-expressing GBM cells suppressed T cell proliferation, while hypoxia restored the proliferation of the T cells, likely due to the reduction in kynurenine levels produced by the GBM cells. Taken together, our data suggest that the regulation of TDO2 expression by HIF1α may be involved in modulating anti-tumor immunity in GBM.

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Section: Discussionmentioning

confidence: 87%

Hypoxia Inducible Factor 1α Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma

et al. 2019

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“…Under tumor conditions however, hypoxia and HIF-1α seem to drive the development and function of immunosuppressive myeloid cells like TAMs and MDSCs (23, 60, 61). Correspondingly, a recent study showed that overexpression of HIF-1α in myeloid cells leads to diminished transplant rejection and induction of a regulatory phenotype in myeloid cells in a model of heart transplantation (62). To our knowledge, our study is the first describing an impact of myeloid HIF-1α-expression on pregnancy outcome.…”

Section: Resultsmentioning

confidence: 99%

HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice

et al. 2019

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Abortions are the most important reason for unintentional childlessness. During pregnancy, maternal immune cells are in close contact to cells of the semi-allogeneic fetus. Dysregulation of the maternal immune system leading to defective adaptation to pregnancy often plays a role in pathogenesis of abortions. Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress functions of other immune cells, especially T-cells, thereby negatively affecting diseases such as cancer, sepsis or trauma. They seem, however, also necessary for maintenance of maternal-fetal tolerance. Mechanisms regulating MDSC expansion and function during pregnancy are only incompletely understood. In tumor environment, hypoxia is crucial for MDSC accumulation and activation. Hypoxia is also important for early placenta and embryo development. Effects of hypoxia are mediated through hypoxia-inducible factor 1α (HIF-1α). In the present study we aimed to examine the role of HIF-1α in myeloid cells for MDSC accumulation and MDSC function during pregnancy and for pregnancy outcome. We therefore used a mouse model with targeted deletion of HIF-1α in myeloid cells (myeloid HIF-KO) and analyzed blood, spleens and uteri of pregnant mice at gestational day E 10.5 in comparison to non-pregnant animals and wildtype (WT) animals. Further we analyzed pregnancy success by determining rates of failed implantation and abortion in WT and myeloid HIF-KO animals. We found that myeloid HIF-KO in mice led to an abrogated MDSC accumulation in the pregnant uterus and to impaired suppressive activity of MDSC. While expression of chemokine receptors and integrins on MDSC was not affected by HIF-1α, myeloid HIF-KO led to increased apoptosis rates of MDSC in the uterus. Myeloid-HIF-KO resulted in increased proportions of non-pregnant animals after positive vaginal plug and increased abortion rates, suggesting that activation of HIF-1α dependent pathways in MDSC are important for maintenance of pregnancy.

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“…In addition, myeloid‐derived suppressor cells reduced T‐cell proliferation. Ultimately, HIF signaling reduced acute rejection and ischemia‐reperfusion injury leading to prolonged allograft survival 185 …”

Section: Hif‐controlled Myeloid Cell Functions—lessons From Animal Experimentsmentioning

confidence: 99%

“…Ultimately, HIF signaling reduced acute rejection and ischemia-reperfusion injury leading to prolonged allograft survival. 185 Synovial tissue from rheumatoid arthritis patients 161,186 and experimental arthritis mice 5 both up-regulated HIFs and myeloid-specific HIF-1𝛼 and HIF-2𝛼 gene deficiency alleviated inflammation in a murine rheumatoid arthritis model. 7,186 Neutrophils isolated from rheumatoid arthritis patients showed enhanced PHD2 and PHD3 mRNA expression in line with induction of proinflammatory HIF target genes.…”

Section: Hif-1𝜶 Improves Myeloid Cell Functions In Infectious and Noninfectious Inflammation Modelsmentioning

confidence: 99%

Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets

Kling

Schreiber

Kettritz

2020

Journal of Leukocyte Biology

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Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent and a constitutive subunit. The stability of HIF-1 and HIF-2 is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1 and HIF-2 modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1 enables efficient infection defense by myeloid cells. HIF-2 delays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders. K E Y W O R D S hypoxia-inducible factor, hypoxia, innate immunity, myeloid cells This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Hypoxia-inducible factor controls immunoregulatory properties of myeloid cells in mouse cardiac allografts - an experimental study

Cited by 8 publications

References 33 publications

Hypoxia Inducible Factor 1α Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma

Hypoxia Inducible Factor 1α Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma

HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice

Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets

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