The Role of HIF in Immunity and Inflammation

McGettrick, Anne F.; O’Neill, Luke A.J.

doi:10.1016/j.cmet.2020.08.002

Cited by 429 publications

(298 citation statements)

References 169 publications

(229 reference statements)

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“…Bolstering these results, the HIF-activator cobalt(II) chloride (60) robustly decreased FXN (Figure 3E-F), while HIF-1a-specific inhibition by siRNA reversed this effect (Figure 3G). Inflammatory cytokines (such as IL-1b) are known to drive expression of HIF-a even under normoxic conditions (61), and more broadly, HIF-dependent processes are known to serve as an important stress response in inflammatory diseases (62). Reinforcing this idea, IL1-btreated PAECs exhibited increased HIF1A transcript levels (Supplemental Figure 3C), suggesting HIF-driven FXN reduction may be a common mechanism across hypoxic and inflammatory triggers.…”

Section: Hif-a Controls Ctcf To Down-regulate Endothelial Fxnmentioning

confidence: 78%

Frataxin deficiency promotes endothelial senescence in pulmonary hypertension

Culley¹,

Zhao²,

Tai³

et al. 2021

Journal of Clinical Investigation

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Section: Hif-a Controls Ctcf To Down-regulate Endothelial Fxnmentioning

confidence: 78%

Frataxin deficiency promotes endothelial senescence in pulmonary hypertension

Culley¹,

Zhao²,

Tai³

et al. 2021

Journal of Clinical Investigation

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“…HIF is a transcription factor that not only responds to hypoxia but also is activated by some non-hypoxic stimuli, including bacterial lipopolysaccharide, ROS, TNF-α, and IL-18 [ 52 , 53 ]. HIF-1α plays an important role in metabolic disorders and inflammation [ 54 ]. High glucose increases HIF-1α expression, and subsequently promotes inflammation and fibrosis in rat glomerular mesangial cells [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Selenium deficiency induces spleen pathological changes in pigs by decreasing selenoprotein expression, evoking oxidative stress, and activating inflammation and apoptosis

Sun

Zhang

et al. 2021

J Animal Sci Biotechnol

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Background The immune system is one aspect of health that is affected by dietary selenium (Se) levels and selenoprotein expression. Spleen is an important immune organ of the body, which is directly involved in cellular immunity. However, there are limited reports on Se levels and spleen health. Therefore, this study established a Se-deficient pig model to investigate the mechanism of Se deficiency-induced splenic pathogenesis. Methods Twenty-four pure line castrated male Yorkshire pigs (45 days old, 12.50 ± 1.32 kg, 12 full-sibling pairs) were divided into two equal groups and fed Se-deficient diet (0.007 mg Se/kg) or Se-adequate diet (0.3 mg Se/kg) for 16 weeks. At the end of the trial, blood and spleen were collected to assay for erythroid parameters, the osmotic fragility of erythrocytes, the spleen index, histology, terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining, Se concentrations, the selenogenome, redox status, and signaling related inflammation and apoptosis. Results Dietary Se deficiency decreased the erythroid parameters and increased the number of osmotically fragile erythrocytes (P < 0.05). The spleen index did not change, but hematoxylin and eosin and TUNEL staining indicated that the white pulp decreased, the red pulp increased, and splenocyte apoptosis occurred in the Se deficient group. Se deficiency decreased the Se concentration and selenoprotein expression in the spleen (P < 0.05), blocked the glutathione and thioredoxin antioxidant systems, and led to redox imbalance. Se deficiency activated the NF-κB and HIF-1α transcription factors, thus increasing pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17, and TNF-α), decreasing anti-inflammatory cytokines (IL-10, IL-13, and TGF-β) and increasing expression of the downstream genes COX-2 and iNOS (P < 0.05), which in turn induced inflammation. In addition, Se-deficiency induced apoptosis through the mitochondrial pathway, upregulated apoptotic genes (Caspase3, Caspase8, and Bak), and downregulated antiapoptotic genes (Bcl-2) (P < 0.05) at the mRNA level, thus verifying the results of TUNEL staining. Conclusions These results indicated that Se deficiency induces spleen injury through the regulation of selenoproteins, oxidative stress, inflammation and apoptosis.

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“…Apart of the activation of NLRP3, high levels of mtROS are also involved in other immunological mechanisms involved in inflammation such as hypoxia inducible factor 1 alpha (HIF1α) and NF-κB (Brunelle et al, 2005). Activation of HIF1α by mtROS can induce the expression of one of its gene targets, the cytokine IL1β resulting in a proinflammatory phenotype (McGettrick and O'Neill, 2020;Tannahill et al, 2013). On the other hand, mtROS induce NF-κB-dependent inflammation (Herb et al, 2019), although in a regulatory feedback, induction of NF-κB by mtROS can also act as a signal to induce the removal of dysfunctional mitochondria that would reduce inflammation (Zhong et al, 2016).…”

Section: Mitochondrial Dysfunction In Inflammatory Responsementioning

confidence: 99%

Age-related mitochondrial dysfunction as a key factor in COVID-19 disease

Fernández-Ayala

Navas

López-Lluch

2020

Experimental Gerontology

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SARS-CoV-2 causes a severe pneumonia (COVID-19) that affects essentially elderly people. In COVID-19, macrophage infiltration into the lung causes a rapid and intense cytokine storm leading finally to a multi-organ failure and death. Comorbidities such as metabolic syndrome, obesity, type 2 diabetes, lung and cardiovascular diseases, all of them age-associated diseases, increase the severity and lethality of COVID-19. Mitochondrial dysfunction is one of the hallmarks of aging and COVID-19 risk factors. Dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation. This review discuss how mitochondrial dysfunction is associated with defective immune response in aging and different age-related diseases, and with many of the comorbidities associated with poor prognosis in the progression of COVID-19. We suggest here that chronic inflammation caused by mitochondrial dysfunction is responsible of the explosive release of inflammatory cytokines causing severe pneumonia, multi-organ failure and finally death in COVID-19 patients. Preventive treatments based on therapies improving mitochondrial turnover, dynamics and activity would be essential to protect against COVID-19 severity.

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The Role of HIF in Immunity and Inflammation

Cited by 429 publications

References 169 publications

Frataxin deficiency promotes endothelial senescence in pulmonary hypertension

Frataxin deficiency promotes endothelial senescence in pulmonary hypertension

Selenium deficiency induces spleen pathological changes in pigs by decreasing selenoprotein expression, evoking oxidative stress, and activating inflammation and apoptosis

Age-related mitochondrial dysfunction as a key factor in COVID-19 disease

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