NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells

Cummins, Eoin P.; Oliver, Kathryn M.; Lenihan, Colin R.; Fitzpatrick, Susan F.; Brüning, Ulrike; Scholz, Carsten C.; Slattery, Craig; Leonard, Martin O.; McLoughlin, Paul; Taylor, Cormac T.

doi:10.4049/jimmunol.1000701

Cited by 92 publications

(103 citation statements)

References 26 publications

(48 reference statements)

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“…Furthermore, the association between hypoxia and other key aspects of the inflammatory microenvironment such as the prevailing cytokine/chemokine milieu and altered carbon dioxide levels and associated changes in pH need to be considered (122,123). Finally, comparative studies of intermittent versus sustained patterns of hypoxia in immune cells will strengthen our understanding of the role of physiologically relevant patterns of hypoxic exposure during inflammation.…”

Section: Perspectivesmentioning

confidence: 99%

Hypoxia-dependent regulation of inflammatory pathways in immune cells

Taylor¹,

Doherty²,

Fallon³

et al. 2016

Journal of Clinical Investigation

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166

131

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Section: Perspectivesmentioning

confidence: 99%

Hypoxia-dependent regulation of inflammatory pathways in immune cells

Taylor¹,

Doherty²,

Fallon³

et al. 2016

Journal of Clinical Investigation

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166

131

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“…Whole-cell, nuclear and cytosolic extracts were generated in either normoxia or hypoxia according to previously published protocols [30,31]. Protein concentration was quantified using a Bradford assay, and samples were normalised accordingly.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Protein concentration was quantified using a Bradford assay, and samples were normalised accordingly. Samples were separated by SDS-PAGE and immunoblotted as described previously [30,31] using the following primary Abs and dilutions: HIF-1# (1:250; BD Pharmingen), "-actin (1:10,000; Sigma) and TATA box binding protein (TBP; 1:2500; Abcam).…”

Section: Western Blot Analysismentioning

confidence: 99%

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Brüning

Fitzpatrick

Frank

et al. 2011

Cell. Mol. Life Sci.

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The oxygen-sensitive transcription factor Hypoxia Inducible Factor (HIF) is a key regulator of gene expression during adaptation to hypoxia. Crucially, inflamed tissue often displays regions of prominent hypoxia. Recent studies have shown HIF signalling is intricately linked to that of the pro-inflammatory transcription factor Nuclear factor kappa B (NF!B) during hypoxic inflammation. Here we describe the relative temporal contributions of each to hypoxia-induced inflammatory gene expression and investigate the level of crosstalk between the two pathways using a novel Gaussia princeps luciferase (Gluc) reporter system. Under the control of an active promoter, Gluc is expressed and secreted into the cell culture media, where it can be sampled and measured over time. Thus Gluc constructs under the control of either HIF or NF!B were used to resolve their temporal transcriptional dynamics in response to hypoxia and to cytokine stimuli respectively. We also investigated the interactions between HIF and NF!B activities using a construct containing the sequence from the promoter of the inflammatory gene cyclooxygenase 2 (COX-2), which includes functionally active binding sites for both HIF and NF!B. Finally, based on our experimental data, we constructed a mathematical model of the binding affinities of HIF and NF!B to their respective response elements to analyse transcriptional crosstalk. Taken together, these data reveal distinct temporal HIF and NF!B transcriptional activities in response to hypoxic inflammation. Furthermore, we demonstrate synergistic activity between these two transcription factors on the regulation of the COX-2 promoter, implicating a coordinated role for both HIF and NF!B in the expression of COX-2 in hypoxic inflammation.

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“…For example, a host inspiring air with a high F CO2 might develop hypercapnia with high levels of CO 2 and bicarbonate in the blood (Henderson and Haggard, 1918), and inspiring high F CO2 also changes gene expression of hosts, including genes associated with immune function (Cummins et al, 2010;Taylor and Cummins, 2011). These and other changes in host physiology might affect parasites by changing the nutritional value of the blood, similar to what happens to phytophagous insects when high F CO2 indirectly affects insect fitness by altering the nutritional quality of host plants (Fajer et al, 1989;Coviella and Trumble, 1999), but this idea would have to be tested directly.…”

Section: Discussionmentioning

confidence: 99%

“…We are inclined to believe that the first explanation is correct because it is the simplest. However, CO 2 exposure can alter expression of transcription factors (Cummins et al, 2010;Taylor and Cummins, 2011) and can alter biochemical pathways including NADPH production (Friedlander et al, 1984). Even short-term exposure to .…”

Section: Discussionmentioning

confidence: 99%

Flea fitness is reduced by high fractional concentrations of CO2 that simulate levels found in their hosts' burrows

Downs

Pinshow

Khokhlova

et al. 2015

Journal of Experimental Biology

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Nidicolous ectoparasites such as fleas and gamasid mites that feed on small and medium-sized mammals spend much of their time in their hosts' burrows, which provide an environment for living, and often feeding, to their pre-imaginal and/or adult stages. Thus, these ectoparasites should be adapted to environmental conditions in burrows, including high fractional concentrations of CO 2 (F CO2 ). We examined how a high F CO2 (0.04) affected survival and reproductive success of a hematophagous ectoparasite of burrowing rodents using fleas Xenopsylla ramesis and Sundevall's jirds Meriones crassus. In the first experiment, fleas fed on hosts housed in high-CO 2 (F CO2 =0.04) or atmospheric-CO 2 (F CO2 ≈0.0004) air, and were allowed to breed. In a second experiment, fleas were maintained in high CO 2 or CO 2 -free air with no hosts to determine how CO 2 levels affect survival and activity levels. We found that at high F CO2 fleas laid fewer eggs, reducing reproductive success. In addition, at high F CO2 , activity levels and survival of fleas were reduced. Our results indicate that fleas do not perform well in the F CO2 used in this experiment. Previous research indicated that the type and intensity of the effects of CO 2 concentration on the fitness of an insect depend on the F CO2 used, so we advise caution when generalizing inferences drawn to insects exposed to other F CO2 . If, however, F CO2 found in natural mammal burrows brings about reduced fitness in fleas in general, then burrowing hosts may benefit from reduced parasite infestation if burrow air F CO2 is high.

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NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells

Abstract: Material

Cited by 92 publications

References 26 publications

Hypoxia-dependent regulation of inflammatory pathways in immune cells

Hypoxia-dependent regulation of inflammatory pathways in immune cells

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Flea fitness is reduced by high fractional concentrations of CO2 that simulate levels found in their hosts' burrows

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