Hypoxia suppresses the production of matrix metalloproteinases and the migration of humanmonocyte‐derived dendritic cells

Zhao, Wenran; Darmanin, Stephanie; Fu, Qiang; Chen, Jian; Cui, Hongyan; Wang, Jingxin; Okada, Futoshi; Hamada, Jun Ichi; Hattori, Yuu Ichi; Kondo, Takeshi; Hamuro, Junji; Asaka, Masahiro; Kobayashi, Masanobu

doi:10.1002/eji.200526262

Cited by 41 publications

(41 citation statements)

References 38 publications

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“…It was reported that hypoxia inhibited the migratory capacity of DCs through extracellular matrix by reducing matrix metalloproteinase-9 expression and augmenting the protease inhibitor tissue inhibitor of metalloproteinase 1 (51,52). We observed that there is no intrinsic defect in the migration of Hi-DCs, which respond more than iDCs to an appropriate stimulus in the absence of an extracellular matrix barrier as it occurs in the Transwell assay.…”

Section: Hypoxia and Differentiation Of Dendritic Cells Mol Cancer Resupporting

confidence: 46%

Transcriptome of Hypoxic Immature Dendritic Cells: Modulation of Chemokine/Receptor Expression

Ricciardi

Elia

Cappello

et al. 2008

Molecular Cancer Research

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Hypoxia is a condition of low oxygen tension occurring in inflammatory tissues. Dendritic cells (DC) are professional antigen-presenting cells whose differentiation, migration, and activities are intrinsically linked to the microenvironment. DCs will home and migrate through pathologic tissues before reaching their final destination in the lymph node. We studied the differentiation of human monocytes into immature DCs (iDCs) in a hypoxic microenvironment. We generated iDC in vitro under normoxic (iDCs) or hypoxic (Hi-DCs) conditions and examined the hypoxia-responsive element in the promoter, gene expression, and biochemical KEGG pathways. Hi-DCs had an interesting phenotype represented by up-regulation of genes associated with cell movement/migration. In addition, the Hi-DC cytokine/receptor pathway showed a dichotomy between down-regulated chemokines and up-regulated chemokine receptor mRNA expression. We showed that CCR3, CX3CR1, and CCR2 are hypoxia-inducible genes and that CCL18, CCL23, CCL26, CCL24, and CCL14 are inhibited by hypoxia. A strong chemotactic response to CCR2 and CXCR4 agonists distinguished Hi-DCs from iDCs at a functional level. The hypoxic microenvironment promotes the differentiation of Hi-DCs, which differs from iDCs for gene expression profile and function. The most prominent characteristic of Hi-DCs is the expression of a mobility/migratory rather than inflammatory phenotype. We speculate that Hi-DCs have the tendency to leave the hypoxic tissue and follow the chemokine gradient toward normoxic areas where they can mature and contribute to the inflammatory process. (Mol Cancer Res 2008;6(2):175 -85)

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Section: Hypoxia and Differentiation Of Dendritic Cells Mol Cancer Resupporting

confidence: 46%

Transcriptome of Hypoxic Immature Dendritic Cells: Modulation of Chemokine/Receptor Expression

Ricciardi

Elia

Cappello

et al. 2008

Molecular Cancer Research

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“…Our results contribute to explain the controversial findings in the literature concerning the effect of hypoxia on MMP-9 levels. MMP-9 production was shown to be downregulated by hypoxia in human monocyte-derived dendritic cells 49 but upregulated in both tumoral 50 and cardiac muscle cells. 51 Both Pyk2 phosphorylation 52 and ROS 53 may underlie the ability of hypoxia to activate NF-κβ.…”

Section: Discussionmentioning

confidence: 98%

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Revuelta‐López

Castellano

Roura

et al. 2013

ATVB

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Objective— Hypoxia disturbs vascular function by promoting extracellular matrix remodeling. Extracellular matrix integrity and composition are modulated by metalloproteinases (MMPs). Our aim was to investigate the role of low-density lipoprotein receptor–related protein 1 (LRP1) in regulating MMP-9/MMP-2 activation and vascular smooth muscle cells (VSMCs) migration in response to hypoxia, and to elucidate the LRP1-signaling pathways involved in this process. Approach and Results— Western blot analysis showed that hypoxia induced a sustained phosphorylation of proline-rich tyrosine kinase 2 concomitantly with LRP1 overexpression in human VSMCs (hVSMCs). Deletion of LRP1 using small-interfering RNA technology or treatment of hVSMCs with the Src family kinase inhibitor PP2 impaired hypoxia-induced phosphorylation of proline-rich tyrosine kinase 2 levels. Coimmunoprecipitation experiments showed that the higher amounts of phosphorylation of proline-rich tyrosine kinase 2/LRP1β immunoprecipitates in hypoxic hVSMCs were abolished in PP2-treated hVSMCs. Both LRP1 silencing and PP2 treatment were highly effective in the prevention of hypoxia-induced MMP-9 activation and hVSMC migration. Cellular subfractionation experiments revealed that PP2 effects may be caused by impairment of hypoxia-induced nuclear factor-κβ translocation to the nucleus. ELISA measurements showed that LRP1 silencing but not PP2 treatment increased interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1 secretion by hypoxic hVSMCs. Conclusions— Our findings determine a crucial role of LRP1-mediated Pyk2 phosphorylation on hypoxia-induced MMP-9 activation and hVSMC migration and therefore in hypoxia-induced vascular remodeling. Both LRP1 silencing and PP2 treatments also influence hypoxia-induced proinflammatory effects in hVSMCs. Therefore, further studies are required to establish therapeutical strategies that efficiently modulate vascular remodeling and inflammation associated with hypoxia-vascular diseases.

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“…The potentially important impact of the local oxygen tension in inflamed tissues on DC regulation is still largely unknown. Two reports (8,9) suggested a reduced migratory capacity of human monocyte-derived DC differentiated under hypoxia, but further evidence for functional effects of hypoxia on DC biology is lacking to date. In particular, the effect of hypoxia on the capability of DC to induce immune responses has not been analyzed yet.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Hypoxia and Hypoxia-Inducible Factor-1α Modulate Lipopolysaccharide-Induced Dendritic Cell Activation and Function

Jantsch

Chakravortty

Turza

et al. 2008

The Journal of Immunology

358

351

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Dendritic cells (DC) play a key role in linking innate and adaptive immunity. In inflamed tissues, where DC become activated, oxygen tensions are usually low. Although hypoxia is increasingly recognized as an important determinant of cellular functions, the consequences of hypoxia and the role of one of the key players in hypoxic gene regulation, the transcription factor hypoxia inducible factor 1α (HIF-1α), are largely unknown. Thus, we investigated the effects of hypoxia and HIF-1α on murine DC activation and function in the presence or absence of an exogenous inflammatory stimulus. Hypoxia alone did not activate murine DC, but hypoxia combined with LPS led to marked increases in expression of costimulatory molecules, proinflammatory cytokine synthesis, and induction of allogeneic lymphocyte proliferation compared with LPS alone. This DC activation was accompanied by accumulation of HIF-1α protein levels, induction of glycolytic HIF target genes, and enhanced glycolytic activity. Using RNA interference techniques, knockdown of HIF-1α significantly reduced glucose use in DC, inhibited maturation, and led to an impaired capability to stimulate allogeneic T cells. Alltogether, our data indicate that HIF-1α and hypoxia play a crucial role for DC activation in inflammatory states, which is highly dependent on glycolysis even in the presence of oxygen.

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Hypoxia suppresses the production of matrix metalloproteinases and the migration of humanmonocyte‐derived dendritic cells

Cited by 41 publications

References 38 publications

Transcriptome of Hypoxic Immature Dendritic Cells: Modulation of Chemokine/Receptor Expression

Transcriptome of Hypoxic Immature Dendritic Cells: Modulation of Chemokine/Receptor Expression

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Hypoxia and Hypoxia-Inducible Factor-1α Modulate Lipopolysaccharide-Induced Dendritic Cell Activation and Function

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