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Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through β2-Adrenergic Receptor Signaling

Leigh, Nicholas D LU orcid ; Kokolus, Kathleen M ; O'Neill, Rachel E ; Du, Wei ; Eng, Jason W-L ; Qiu, Jingxin ; Chen, George L ; McCarthy, Philip L ; Farrar, J David and Cao, Xuefang , et al. (2015) In Journal of immunology 195(10). p.54-5045
Abstract

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼ 22°C) are more... (More)

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼ 22°C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (∼ 30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through β-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a β2-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a β2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using β2-adrenergic receptor-deficient (β2-AR(-/-)) mice, we found that it is host cell β2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of β-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adrenergic beta-2 Receptor Antagonists/pharmacology, Animals, Female, Graft vs Host Disease/genetics, Hematopoietic Stem Cell Transplantation, Hot Temperature, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Receptors, Adrenergic, beta-2/genetics, Signal Transduction/drug effects, Stress, Physiological/genetics
in
Journal of immunology
volume
195
issue
10
pages
10 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:84958652738
  • pmid:26459348
ISSN
1550-6606
DOI
10.4049/jimmunol.1500700
language
English
LU publication?
no
additional info
Copyright © 2015 by The American Association of Immunologists, Inc.
id
5b490218-b00d-4a1f-baf3-5eb340ec38b1
date added to LUP
2020-04-30 23:14:10
date last changed
2022-09-24 06:12:37
@article{5b490218-b00d-4a1f-baf3-5eb340ec38b1,
  abstract     = {{<p>Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼ 22°C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (∼ 30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through β-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a β2-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a β2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using β2-adrenergic receptor-deficient (β2-AR(-/-)) mice, we found that it is host cell β2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of β-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.</p>}},
  author       = {{Leigh, Nicholas D and Kokolus, Kathleen M and O'Neill, Rachel E and Du, Wei and Eng, Jason W-L and Qiu, Jingxin and Chen, George L and McCarthy, Philip L and Farrar, J David and Cao, Xuefang and Repasky, Elizabeth A}},
  issn         = {{1550-6606}},
  keywords     = {{Adrenergic beta-2 Receptor Antagonists/pharmacology; Animals; Female; Graft vs Host Disease/genetics; Hematopoietic Stem Cell Transplantation; Hot Temperature; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Receptors, Adrenergic, beta-2/genetics; Signal Transduction/drug effects; Stress, Physiological/genetics}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{10}},
  pages        = {{54--5045}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of immunology}},
  title        = {{Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through β2-Adrenergic Receptor Signaling}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1500700}},
  doi          = {{10.4049/jimmunol.1500700}},
  volume       = {{195}},
  year         = {{2015}},
}