The critical role of mast cell-derived hypoxia-inducible factor-1α in regulating mast cell function

Abstract The oxygen-sensing transcription factor hypoxia-inducible factor-1α (HIF-1α) plays a critical role in the regulation of myeloid cell function. The mechanisms of regulation are not well understood, nor are the phenotypic consequences of HIF modulation in the context of neutrophilic inflammation. Species conservation across higher metazoans enables the use of the genetically tractable and transparent zebrafish (Danio rerio) embryo to study in vivo resolution of the inflammatory response. Using both a pharmacologic approach known to lead to stabilization of HIF-1α, and selective genetic manipulation of zebrafish HIF-1α homologs, we sought to determine the roles of HIF-1α in inflammation resolution. Both approaches reveal that activated Hif-1α delays resolution of inflammation after tail transection in zebrafish larvae. This delay can be replicated by neutrophil-specific Hif activation and is a consequence of both reduced neutrophil apoptosis and increased retention of neutrophils at the site of tissue injury. Hif-activated neutrophils continue to patrol the injury site during the resolution phase, when neutrophils would normally migrate away. Site-directed mutagenesis of Hif in vivo reveals that hydroxylation of Hif-1α by prolyl hydroxylases critically regulates the Hif pathway in zebrafish neutrophils. Our data demonstrate that Hif-1α regulates neutrophil function in complex ways during inflammation resolution in vivo.

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Role of hypoxia-inducible factor 1α in modulating cobalt-induced lung inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00252.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. L139-L147 ◽

Cited By ~ 22

Author(s):

Yogesh Saini ◽

Kyung Y. Kim ◽

Ryan Lewandowski ◽

Lori A. Bramble ◽

Jack R. Harkema ◽

...

Keyword(s):

Cellular Response ◽

Cell Function ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Neutrophil Infiltration ◽

Oxygen Deficit ◽

Th2 Response ◽

Mucus Cell ◽

Cobalt Exposure

Hypoxia plays an important role in development, cellular homeostasis, and pathological conditions, such as cancer and stroke. There is also growing evidence that hypoxia is an important modulator of the inflammatory process. Hypoxia-inducible factors (HIFs) are a family of proteins that regulate the cellular response to oxygen deficit, and loss of HIFs impairs inflammatory cell function. There is little known, however, about the role of epithelial-derived HIF signaling in modulating inflammation. Cobalt is capable of eliciting an allergic response and promoting HIF signaling. To characterize the inflammatory function of epithelial-derived HIF in response to inhaled cobalt, a conditional lung-specific HIF1α, the most ubiquitously expressed HIF, deletion mouse, was created. Control mice showed classic signs of metal-induced injury following cobalt exposure, including fibrosis and neutrophil infiltration. In contrast, HIF1α-deficient mice displayed a Th2 response that resembled asthma, including increased eosinophilic infiltration, mucus cell metaplasia, and chitinase-like protein expression. The results suggest that epithelial-derived HIF signaling has a critical role in establishing a tissue's inflammatory response, and compromised HIF1α signaling biases the tissue towards a Th2-mediated reaction.

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Nitric Oxide Is a Factor in the Stabilization of Hypoxia-Inducible Factor-1α in Cancer: Role of Free Radical Formation

Cancer Research ◽

10.1158/0008-5472.can-05-0333 ◽

2006 ◽

Vol 66 (2) ◽

pp. 770-774 ◽

Cited By ~ 76

Author(s):

Marisol Quintero ◽

Peter A. Brennan ◽

Gareth J. Thomas ◽

Salvador Moncada

Keyword(s):

Nitric Oxide ◽

Free Radical ◽

Hypoxia Inducible Factor ◽

Radical Formation ◽

Hypoxia Inducible Factor 1Α ◽

Free Radical Formation

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Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction

AJP Renal Physiology ◽

10.1152/ajprenal.00116.2021 ◽

2021 ◽

Author(s):

Goutham Pattabiraman ◽

Ashlee J Bell-Cohn ◽

Stephen F. Murphy ◽

Daniel J Mazur ◽

Anthony J Schaeffer ◽

...

Keyword(s):

Mast Cell ◽

Smooth Muscle ◽

Mast Cells ◽

Cell Activation ◽

Cell Function ◽

Critical Role ◽

Smooth Muscle Contraction ◽

Urinary Dysfunction ◽

Mast Cell Activation ◽

Prostate Inflammation

Intraurethral inoculation of mice with uropathogenic E. coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of mast cell stabilizer (MCS), cromolyn sodium, and the histamine 1 receptor antagonist (H1RA), cetirizine di-hydrochloride, in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.

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