A Myeloid Hypoxia-inducible Factor 1α-Krüppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis

Mahabeleshwar, Ganapati H.; Qureshi, Muhammad Awais; Takami, Yoichi; Sharma, Nikunj; Lingrel, Jerry B.; Jain, Mukesh K.

doi:10.1074/jbc.m111.312702

Cited by 39 publications

(43 citation statements)

References 33 publications

(31 reference statements)

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“…However, Kruppel-like factor 2 (KLF2) could be considered a potential candidate in light of recent reports revealing its role in PHD-independent HIF-1␣ proteasomal degradation, through direct disruption of the HSP90/HIF-1␣ complex (22). In addition, signaling pathways of KLF2 and HIF-1 have been recently shown to be interconnected upon bacterial infection (30,31). A second consideration could be direct interference with the ubiquitination stage of protein degradation, as evidence has already revealed that microbial compounds could target this pathway (45).…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1α Degradation

et al. 2012

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bThe transcription factor hypoxia-inducible factor 1 (HIF-1) has recently emerged to be a crucial regulator of the immune response following pathogen perception, including the response to the important human pathogen Pseudomonas aeruginosa. However, as mechanisms involved in HIF-1 activation by bacterial pathogens are not fully characterized, understanding how bacteria and bacterial compounds impact on HIF-1␣ stabilization remains a major challenge. In this context, we have focused on the effect of secreted factors of P. aeruginosa on HIF-1 regulation. Surprisingly, we found that P. aeruginosa cell-free supernatant significantly repressed HIF-1␣ protein levels. Further characterization revealed that HIF-1␣ downregulation was dependent on a subset of key secreted factors involved in P. aeruginosa pathogenesis, the 2-alkyl-4-quinolone (AQ) quorum sensing (QS) signaling molecules, and in particular the pseudomonas quinolone signal (PQS). Under hypoxic conditions, the AQ-dependent downregulation of HIF-1␣ was linked to the suppressed induction of the important HIF-1 target gene hexokinase II. Furthermore, we demonstrated that AQ molecules directly target HIF-1␣ protein degradation through the 26S-proteasome proteolytic pathway but independently of the prolyl hydroxylase domain (PHD). In conclusion, this is the first report showing that bacterial molecules can repress HIF-1␣ protein levels. Manipulation of HIF-1 signaling by P. aeruginosa AQs could have major consequences for the host response to infection and may facilitate the infective properties of this pathogen.

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1α Degradation

et al. 2012

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“…When mice with conditional Hif1a deletion in the myeloid lineage are challenged with LPS, they exhibit reduced hypothermia and hypotension, along with enhanced survival compared with mice that express myeloid HIF-1α (39). Myeloid HIF-1α deficiency is also protective in a gram-positive endotoxin-induced murine sepsis model (144). Similar to HIF-1α, deletion of myeloid HIF-2α is also protective against sepsis.…”

Section: Hifs In Myeloid Cellsmentioning

confidence: 99%

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Lin¹,

Simon²

2016

Journal of Clinical Investigation

115

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“…51 However, in the face of Gram-positive and Gram-negative septicemia, HIF-1α-deficiency confers protection attributable to attenuation of myeloid cell activation and systemic cytokine release. 52 In contrast to HIF-1α, HIF-2α limits nitric oxide production by induction of Arg1, an enzyme competing for l-arginine substrate availability. Via Arg1, HIF-2α induces ornithine and polyamine or urea production.…”

Section: Hypoxia Inducible Factorsmentioning

confidence: 99%

Transcriptional Control of Macrophage Polarization

Tugal

Liao

Jain

2013

ATVB

Self Cite

305

242

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Abstract-Macrophages are key regulators of many organ systems, including innate and adaptive immunity, systemic metabolism, hematopoiesis, vasculogenesis, malignancy, and reproduction. The pleiotropic roles of macrophages are mirrored by similarly diverse cellular phenotypes. A simplified schema classifies macrophages as M1, classically activated macrophages, or M2, alternatively activated macrophages. These cells are characterized by their expression of cell surface markers, secreted cytokines and chemokines, and transcription and epigenetic pathways. Transcriptional regulation is central to the differential speciation of macrophages, and several major pathways have been described as essential for subset differentiation. In this review, we discuss the transcriptional regulation of macrophages.

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A Myeloid Hypoxia-inducible Factor 1α-Krüppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis

Cited by 39 publications

References 33 publications

Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1α Degradation

Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1α Degradation

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Transcriptional Control of Macrophage Polarization

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