Jin Xi, Zhao Wanke, Kirabo Annet, Park Sung O, Ho Wanting T, Sayeski Peter P, Zhao Zhizhuang J
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and.
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32611.
J Immunol. 2014 Jul 15;193(2):477-84. doi: 10.4049/jimmunol.1301946. Epub 2014 Jun 11.
Pruritus occurs frequently in patients with polycythemia vera (PV), and the pathophysiology of PV-associated pruritus is unclear. We have previously demonstrated that transgenic mice expressing JAK2V617F displayed clear PV-like phenotypes. In the current study, we found frequent occurrence of pruritus with aged JAK2V617F transgenic mice and further investigated the underlying mechanisms by studying mast cells, key players in allergic reactions and anaphylaxis. Massive accumulations of mast cells were observed in the skin of pruritic JAK2V617F transgenic mice. In vitro culture yielded much higher mast cell counts from the bone marrow, spleen, peripheral blood, and peritoneal cavity of JAK2V617F transgenic mice than from controls. Cultured mast cells from JAK2V617F transgenic mice exhibited enhanced proliferative signals, relative resistance to cell death upon growth factor deprivation, and a growth advantage over control cells under suboptimal growth conditions. However, these mast cells displayed normal morphology and contained normal levels of mast cell proteases before and after degranulation. Finally, the JAK2 inhibitor G6 effectively reduced mast cell numbers and alleviated pruritus in JAK2V617F transgenic mice. Collectively, these data demonstrate that mast cells are involved in PV-associated pruritogenesis and that JAK2 inhibitors are potential antipruritus drugs.
真性红细胞增多症（PV）患者经常出现瘙痒症状，而PV相关性瘙痒的病理生理学尚不清楚。我们之前已经证明，表达JAK2V617F的转基因小鼠表现出明显的PV样表型。在当前研究中，我们发现老年JAK2V617F转基因小鼠频繁出现瘙痒症状，并通过研究肥大细胞（过敏反应和过敏症的关键参与者）进一步探究其潜在机制。在瘙痒的JAK2V617F转基因小鼠的皮肤中观察到大量肥大细胞聚集。体外培养显示，JAK2V617F转基因小鼠骨髓、脾脏、外周血和腹腔中的肥大细胞计数远高于对照组。来自JAK2V617F转基因小鼠的培养肥大细胞表现出增强的增殖信号，在生长因子剥夺后对细胞死亡具有相对抗性，并且在次优生长条件下比对照细胞具有生长优势。然而，这些肥大细胞在脱颗粒前后形态正常，肥大细胞蛋白酶水平正常。最后，JAK2抑制剂G6有效减少了JAK2V617F转基因小鼠的肥大细胞数量并减轻了瘙痒症状。总体而言，这些数据表明肥大细胞参与了PV相关性瘙痒的发生，并且JAK2抑制剂是潜在的止痒药物。
