Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through β2-Adrenergic Receptor Signaling.
Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through β2-Adrenergic Receptor Signaling.
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DOI：
10.4049/jimmunol.1500700
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发表时间：
2015-11-15
期刊：
影响因子：
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通讯作者：
Repasky EA
中科院分区：
文献类型：
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作者：
Leigh ND;Kokolus KM;O'Neill RE;Du W;Eng JW;Qiu J;Chen GL;McCarthy PL;Farrar JD;Cao X;Repasky EA
移植物抗宿主病（GVHD）是同种异体造血细胞移植（alloHCT）的主要并发症，异基因造血细胞移植是血液系统疾病的潜在治愈疗法。长期以来，人们一直认为鼠骨髓 (BM) 来源的 T 细胞因其数量和/或表型而不会介导严重的 GVHD。在测试外壳温度对 GVHD 影响的实验过程中，我们发现这种表观电阻是相对较冷的环境外壳温度的函数。小鼠骨髓来源的 T 细胞能够在中性温度下饲养的小鼠中介导严重的 GVHD。具体来说，饲养在IACUC规定的凉爽标准温度（~22°C）的小鼠比饲养在中性温度（~30°C）的小鼠更能抵抗GVHD。我们了解到，这种外壳依赖性免疫抑制的机制与去甲肾上腺素产生增加和β-肾上腺素受体（β-AR）信号传导过度有关，当小鼠受到冷应激时，β-肾上腺素受体（β-AR）信号传导会增加。用 β2-肾上腺素能拮抗剂治疗 22°C 饲养的小鼠可逆转去甲肾上腺素驱动的 GVHD 抑制，并产生与 30°C 饲养的小鼠相似的疾病。相反，在 30°C 饲养的小鼠中，给予 β2-肾上腺素能激动剂可降低 GVHD。在使用β2-肾上腺素能受体缺陷（β2-AR−/−）小鼠的进一步机制研究中，我们发现宿主细胞β2-AR信号传导对于降低GVHD至关重要。这些数据揭示了 β-AR 信号传导的基线水平如何影响小鼠 GVHD，并指出在临床环境中操纵 β2-AR 信号传导以改善 GVHD 的可行性。
Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation (alloHCT), a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow (BM) 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 BM-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at IACUC mandated, cool standard temperatures (~22°C) are more resistant to developing GVHD than 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 (β-AR) 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-AR signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.