Hypoxia-Independent Activation of HIF-1 by Enterobacteriaceae and Their Siderophores

Hartmann, Hanna; Eltzschig, Holger K.; Würz, H; Hantke, Klaus; Rakin, Alexander; Yazdi, Amir S.; Matteoli, Gianluca; Bohn, Erwin; Autenrieth, Ingo B.; Karhausen, Jörn; Neumann, Diana; Colgan, Sean P.; Kempf, Volkhard A. J.

doi:10.1053/j.gastro.2007.12.008

Cited by 125 publications

(129 citation statements)

References 43 publications

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“…Holden et al demonstrated that bacterial siderophores such as enterobactin chelate iron to the extent that HIF is stabilized and HIF target genes are induced (94). Likewise, it was shown that siderophores from a number of bacterial genera (e.g., Salmonella, Yersenia, Enterobacter) are capable of stabilizing HIF (95 (110). Importantly, similar Paneth cell defects have been reported for knockin transgenic mice and CD patients homozygous for the ATG16L1 T300A risk allele (109,111).…”

Section: Host-microbial Metabolism and Tissue Barriermentioning

confidence: 82%

“…Mucosa-associated microbiota are likely also prominent modulators of potential hypoxia-elicited autophagic responses (see Figure 2). Both commensal and pathogenic species have been shown to influence mucosal pO 2 and/or enterocyte HIF signaling (95,121,122), and ablation of epithelial HIF-1 increases susceptibility to pathogen infection in a number of studies (95,121). Reciprocally, intestinal oxygenation directly shapes the composition of gut microbial communities, and oxidative changes in intestinal inflammation may underlie the dysbiosis characteristic of IBD (5).…”

Section: Metabolic Regulation Of Epithelial Autophagymentioning

confidence: 99%

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Oxygen metabolism and barrier regulation in the intestinal mucosa

Glover¹,

Lee²,

Colgan³

2016

Journal of Clinical Investigation

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134

108

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Section: Host-microbial Metabolism and Tissue Barriermentioning

confidence: 82%

Section: Metabolic Regulation Of Epithelial Autophagymentioning

confidence: 99%

Oxygen metabolism and barrier regulation in the intestinal mucosa

Glover¹,

Lee²,

Colgan³

2016

Journal of Clinical Investigation

Self Cite

134

108

View full text Add to dashboard Cite

“…These mice, which fail to adapt to oxygen deprivation, are more susceptible to infections with streptococci (37,38), staphylococci (39), and enteric Yersinia (40). In the case of group A streptococci, the increased susceptibility to infection was associated with the failure of HIF-1a-deficient mice to upregulate the antimicrobial peptide CRAMP, the murine homolog of cathelicidin (39).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages

Nickel

Busch

Mayer

et al. 2012

The Journal of Immunology

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Low oxygen tension is a metabolic hallmark of chronic infection. To investigate the influence of hypoxia on macrophage biology, we analyzed the interaction between the intracellular pathogen Mycobacterium tuberculosis and primary human macrophages. Although the metabolic activity of extracellular M. tuberculosis was reduced at oxygen levels between 0.5 and 10%, the bacilli remained viable throughout the 4 d of culture. Phagocytosis of virulent M. tuberculosis and the pathogen-induced release of inflammatory cytokines by macrophages were not affected by oxygen levels as low as 1%. However, we detected the upregulation of an antimicrobial effector pathway mediated by the vitamin D receptor and human β defensin 2. This finding was functionally relevant, because intracellular mycobacterial growth was inhibited by 58 ± 8% at 1% O2. We conclude that a hypoxic microenvironment, which is characteristic of infected tissue, supports the efficacy of antimicrobial immunity, in part by the upregulation of the antimicrobial peptide human β defensin 2.

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“…For example, in contrast to our acute gut I/R results, HIF-1␣ was found to be protective in more chronic gut injury models utilizing colon-specific HIF-1␣-deficient mice. These models included 2,4,6-trinitrobenzene sulfonic acid -induced colitis (12,37,56), chronic hypoxia (24), and Yersinia enterocolitica orogastric infection (28). In the context of gut I/R injury, one study found that mice administered the hydroxylase inhibitor, dimethyloxalglycine (DMOG) was pro- tective in a localized gut I/R injury model (superior mesenteric artery occlusion for 15 min and 3 h reperfusion), and HIF-1 mediated its protective effects via CD73 (27).…”

Section: Discussionmentioning

confidence: 99%

“…Thus the role of HIF-1, as protective or deleterious, may depend on whether the insult is acute or chronic, the segments of the intestine injured, as well as on whether the loss of HIF-1␣ is partial or total. For example, the chronic studies, where HIF-1 was protective, utilized conditional intestinal and colonic epithelial HIF-1␣ mice (28,37,56), whereas our studies were performed in mice with a partial HIF-1␣ deficiency that involves the entire gut. These differences may be important, since the segment of the gut that is susceptible to acute gut I/R-mediated injury is the distal small intestine (33,69).…”

Section: Discussionmentioning

confidence: 99%

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Feinman

Deitch

Watkins

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

125

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mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 299: G833-G843, 2010. First published August 5, 2010 doi:10.1152/ajpgi.00065.2010.-Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1␣-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1␣ deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1␣ deficiency reduced TNF-␣, IL-1␤, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1␤ mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights. hemorrhagic shock; inflammation; multiple organ dysfunction syndrome; acute lung injury IN PATIENTS SUSTAINING major trauma, the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MODS) is a major clinical problem resulting in 50 -80% of all deaths in surgical intensive care units. Since the pathophysiology of this syndrome remains incompletely understood and therapy remains largely supportive (16), studies focusing on the basic biology of traumainduced SIRS, organ injury/dysfunction, and MODS have been major areas of investigation. These mechanistic studies have generated several working hypotheses, one of which is the gut hypothesis of MODS. A key element in the gut hypothesis of MODS is that a splanchnic ischemia-reperfusion (I/R) insult leading to gut inflammation and loss of barrier function is the initial triggering event that turns the gut into the "motor" of MODS (19). However, the exact mechanisms by which gut I/R leads to intestinal injury and how an intestinal ischemic insult is transduced into a systemic inflammatory response remains incomplete. To date, the majority of the molecular and cellular studies investigating shock-induced gut injury and gut-induced MODS have focused pr...

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Hypoxia-Independent Activation of HIF-1 by Enterobacteriaceae and Their Siderophores

Cited by 125 publications

References 43 publications

Oxygen metabolism and barrier regulation in the intestinal mucosa

Oxygen metabolism and barrier regulation in the intestinal mucosa

Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

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