Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis

Piliponsky, Adrian M.; Chen, Ching-Cheng; Nishimura, Toshihiko; Metz, Martin; Rios, Eon J.; Dobner, Paul R.; Wada, Etsuko; Wada, Keiji; Zacharias, Sherma; Mohanasundaram, Uma M.; Faix, James D.; Åbrink, Magnus; Pejler, Gunnar; Pearl, Ronald G.; Tsai, Mindy; Galli, Stephen J.

doi:10.1038/nm1738

Cited by 120 publications

(112 citation statements)

References 45 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…[1][2][3][4][5][7][8][9][10][11]13 We therefore decided to examine the role of mast cells and mast cell-derived TNF in another model of severe bacterial infection. S. typhimurium is a Gram-negative intracellular pathogen that causes a deadly systemic infection in mice that resembles typhoid fever in humans.…”

Section: Mast Cell-derived Tnf Can Contribute To Bacterial Proliferatmentioning

confidence: 99%

“…Studies conducted using genetically mast cell-deficient (WB/ReJ ϫ C57BL/6)F 1 [1][2][3][4][5][6][7][8][9][10][11][12][13] defined herein as infections that result in relatively low mortality in normal mice. Although mast cells can contribute to host defense against bacteria by multiple direct and indirect mechanisms, [1][2][3][4][5][7][8][9][10][11][12][13] several groups have focused on the potential role of mast cell-derived tumor necrosis factor (TNF) in such settings. [1][2][3][4][5]7 Results obtained in work using TNFdeficient mice 4 or mice in which the actions of TNF are blocked by neutralizing antibodies 1,2 have clearly demonstrated that TNF can have protective functions during some bacterial infections, and that such TNF-dependent effects may include the enhancement of neutrophil recruitment and/or function and the promotion of bacterial clearance.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mast Cell-Derived TNF Can Exacerbate Mortality during Severe Bacterial Infections in C57BL/6-Kit Mice

Piliponsky

Chen

Grimbaldeston

et al. 2010

The American Journal of Pathology

Self Cite

130

174

View full text Add to dashboard Cite

We used mast cell-engrafted genetically mast cell-deficient C57BL/6-Kit W-sh/W-sh mice to investigate the roles of mast cells and mast cell-derived tumor necrosis factor in two models of severe bacterial infection. In these mice, we confirmed findings derived from studies of mast cell-deficient WBB6F 1 -Kit W/W-v mice indicating that mast cells can promote survival in cecal ligation and puncture (CLP) of moderate severity. However, we found that the beneficial role of mast cells in this setting can occur independently of mast cell-derived tumor necrosis factor. By contrast, using mast cell-engrafted C57BL/6-Kit W-sh/W-sh mice, we found that mast cell-derived tumor necrosis factor can increase mortality during severe CLP and can also enhance bacterial growth and hasten death after intraperitoneal inoculation of Salmonella typhimurium. In WBB6F 1 -Kit W-sh/W-sh mice, mast cells enhanced survival during moderately severe CLP but did not significantly change the survival observed in severe CLP. Our findings in three types of genetically mast celldeficient mice thus support the hypothesis that, depending on the circumstances (including mouse strain background, the nature of the mutation resulting in a mast cell deficiency, and type and severity of infection), mast cells can have either no detectable effect or opposite effects on survival during bacterial infections, eg, promoting survival during moderately severe CLP associated with low mortality but, in C57BL/ 6-Kit W-sh/W-sh mice, increasing mortality during severe CLP or infection with S. typhimurium. (Am J Pathol

show abstract

Section: Mast Cell-derived Tnf Can Contribute To Bacterial Proliferatmentioning

confidence: 99%

mentioning

confidence: 99%

Mast Cell-Derived TNF Can Exacerbate Mortality during Severe Bacterial Infections in C57BL/6-Kit Mice

Piliponsky

Chen

Grimbaldeston

et al. 2010

The American Journal of Pathology

Self Cite

130

174

View full text Add to dashboard Cite

show abstract

“…To examine the potential role of NT in fat deposition and obesity, we initially compared NT-deficient mice 10,11 to wild type littermates fed a standard diet (18% kcal from fat) for 6 months. Average body length, small bowel weight and length, villus height and crypt number did not differ between genotypes (Extended Data Fig.…”

mentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

227

237

View full text Add to dashboard Cite

Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

show abstract

“…This alternative approach is particularly interesting for studying the role of a protein whose deficiency induces embryonic lethality in mice, and therefore for which BMCMCs deficient for this protein cannot be generated. Both BMCMCs and ESCMCs can also be transduced in vitro with lentiviruses encoding genes of interest or shRNA to silence genes of interest, before engraftment of these cells into MC-deficient mice 31,33 .…”

Section: Discussionmentioning

confidence: 99%

Analyzing the Functions of Mast Cells <em>In Vivo</em> Using '<em>Mast Cell Knock-in</em>' Mice

Gaudenzio

Sibilano

Starkl

et al. 2015

JoVE

Self Cite

View full text Add to dashboard Cite

Mast cells (MCs) are hematopoietic cells which reside in various tissues, and are especially abundant at sites exposed to the external environment, such as skin, airways and gastrointestinal tract. Best known for their detrimental role in IgE-dependent allergic reactions, MCs have also emerged as important players in host defense against venom and invading bacteria and parasites. MC phenotype and function can be influenced by microenvironmental factors that may differ according to anatomic location and/or based on the type or stage of development of immune responses. For this reason, we and others have favored in vivo approaches over in vitro methods to gain insight into MC functions. Here, we describe methods for the generation of mouse bone marrow-derived cultured MCs (BMCMCs), their adoptive transfer into genetically MC-deficient mice, and the analysis of the numbers and distribution of adoptively transferred MCs at different anatomical sites. This method, named the 'mast cell knock-in' approach, has been extensively used over the past 30 years to assess the functions of MCs and MC-derived products in vivo. We discuss the advantages and limitations of this method, in light of alternative approaches that have been developed in recent years. Video LinkThe video component of this article can be found at

show abstract

Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis

Cited by 120 publications

References 45 publications

Mast Cell-Derived TNF Can Exacerbate Mortality during Severe Bacterial Infections in C57BL/6-Kit Mice

Mast Cell-Derived TNF Can Exacerbate Mortality during Severe Bacterial Infections in C57BL/6-Kit Mice

An obligatory role for neurotensin in high-fat-diet-induced obesity

Analyzing the Functions of Mast Cells <em>In Vivo</em> Using '<em>Mast Cell Knock-in</em>' Mice

Contact Info

Product

Resources

About