Housing temperature-induced stress is suppressing murine Graft-versus-host disease through β2-adrenergic receptor signaling

Nicholas D. Leigh, Kathleen M. Kokolus, Rachel E. O'Neill, Wei Du, Jason W L Eng, Jingxin Qiu, George L. Chen, Philip L. McCarthy, J. David Farrar, Xuefang Cao, Elizabeth A. Repasky

Research output: Contribution to journalArticle

22 Scopus citations

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 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-AR2/2) 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.

Original languageEnglish (US)
Pages (from-to)5045-5054
Number of pages10
JournalJournal of Immunology
Volume195
Issue number10
DOIs
StatePublished - Nov 15 2015

ASJC Scopus subject areas

  • Immunology

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    Leigh, N. D., Kokolus, K. M., O'Neill, R. E., Du, W., Eng, J. W. L., Qiu, J., Chen, G. L., McCarthy, P. L., Farrar, J. D., Cao, X., & Repasky, E. A. (2015). Housing temperature-induced stress is suppressing murine Graft-versus-host disease through β2-adrenergic receptor signaling. Journal of Immunology, 195(10), 5045-5054. https://doi.org/10.4049/jimmunol.1500700