Eltrombopag modulates the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in immune thrombocytopenia
Eltrombopag modulates the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in immune thrombocytopenia
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DOI：
10.1080/09537104.2022.2135694
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发表时间：
2022-10
期刊：
影响因子：
3.3
通讯作者：
Fei Yang;Hui Zong;Feng-fei Li;Shulin Luo;Xiuqun Zhang;Yanli Xu;Xuezhong Zhang
中科院分区：
文献类型：
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作者：
Fei Yang;Hui Zong;Feng-fei Li;Shulin Luo;Xiuqun Zhang;Yanli Xu;Xuezhong Zhang
**摘要** 原发性免疫性血小板减少症（ITP）是一种获得性自身免疫性出血性疾病。免疫耐受的丧失在ITP的发病机制中起着关键作用。单核细胞和巨噬细胞在造血系统恶性肿瘤的病理生理过程中发挥着不可或缺的作用，并且被认为是血小板破坏的关键因素。大约80%的成年ITP患者对皮质类固醇治疗无效或产生依赖，因此需要新的治疗方法。血小板生成素（TPO）受体激动剂（TPO - RAs）已在临床上用于有效治疗ITP，然而，关于TPO - RAs对成年ITP患者单核细胞和巨噬细胞调节作用的了解甚少。在本研究中，我们探究了接受艾曲泊帕治疗的ITP患者单核细胞/巨噬细胞的表型演变及潜在的免疫调节作用。结果显示，ITP患者外周血单核细胞计数与IFN - γ/IL - 4比值呈正相关。此外，ITP巨噬细胞中众多与表型相关的基因呈现出不同的反应，且ITP巨噬细胞表现出更多与M1相关的特征。艾曲泊帕治疗后，ITP患者外周血单核细胞计数和IFN - γ/IL - 4比值显著下降。艾曲泊帕部分逆转了ITP巨噬细胞与M1相关的特征。因此，本研究表明艾曲泊帕恢复了单核细胞动态平衡及相关的Th1/Th2失衡，并部分逆转了ITP巨噬细胞与M1相关的特征，这提示TPO - RAs在调节ITP患者单核细胞/巨噬细胞可塑性方面可能具有重要作用。
**通俗语言总结**
- **研究背景**：原发性免疫性血小板减少症（ITP）是一种获得性自身免疫性出血性疾病。免疫耐受的丧失在ITP的发病机制中起着关键作用。单核细胞和巨噬细胞在造血系统恶性肿瘤的病理生理过程中发挥着不可或缺的作用，并且被认为是血小板破坏的关键因素。大约80%的成年ITP患者对皮质类固醇治疗无效或产生依赖，因此需要新的治疗方法。血小板生成素（TPO）受体激动剂（TPO - RAs）已在临床上用于有效治疗ITP，然而，关于TPO - RAs对ITP患者单核细胞和巨噬细胞调节作用的了解甚少。
- **新发现**：在本研究中，我们探究了接受艾曲泊帕治疗的ITP患者单核细胞/巨噬细胞的表型演变及潜在的免疫调节作用。ITP患者外周血单核细胞的扩增与IFN - γ/IL - 4比值呈正相关。ITP巨噬细胞表现出更多与M1相关的特征。艾曲泊帕治疗后，ITP患者外周血单核细胞计数和IFN - γ/IL - 4比值显著下降。艾曲泊帕部分逆转了ITP巨噬细胞与M1相关的特征。
- **研究意义**：本研究为TPO - RAs在调节ITP患者单核细胞/巨噬细胞可塑性方面可能具有重要作用提供了证据。
Abstract Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease. Loss of immune tolerance plays a crucial role in the pathogenesis of ITP. Monocytes and macrophages play an indispensable role in the pathophysiology of hematopoietic malignancies and have been implicated as key players in platelet destruction. Approximately 80% of adult patients with ITP exhibit corticosteroid treatment failure or become dependent, requiring novel therapy. Thrombopoietin (TPO) receptor agonists (TPO-RAs) have been used clinically to manage ITP effectively, however, little is known about the effect of TPO-RAs on monocyte and macrophage modulation in adult ITP. In this study, we investigated the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in ITP patients receiving eltrombopag therapy. Results showed that the peripheral monocyte count positively correlated with IFN-γ/IL-4 ratio in ITP patients. Moreover, numerous phenotype-associated genes in ITP macrophages exhibited diverse responses, and ITP macrophages exhibited more M1-related characteristics. After eltrombopag therapy, the peripheral monocyte count and IFN-γ/IL-4 ratio significantly decreased in ITP patients. M1-related characteristics of ITP macrophages were partially reversed by eltrombopag. Therefore, this study revealed eltrombopag restored the monocyte dynamics and the associated Th1/Th2 imbalance, and partially reversed the M1-related characteristics of the ITP macrophages, which suggest the potential vital roles of TPO-RAs in regulating the monocyte/macrophage plasticity in ITP. Plain Language Summary What is the context? Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease. Loss of immune tolerance plays a crucial role in the pathogenesis of ITP. Monocytes and macrophages play an indispensable role in the pathophysiology of hematopoietic malignancies and have been implicated as key players in platelet destruction. Approximately 80% of adult patients with ITP exhibit corticosteroid treatment failure or become dependent, requiring novel therapy. Thrombopoietin (TPO) receptor agonists (TPO-RAs) have been used clinically to manage ITP effectively, however, little is known about the effect of TPO-RAs on monocyte and macrophage modulation in ITP. What is new? In this study, we investigated the phenotypic evolution and potential immunomodula-tory roles of monocytes/macrophages in ITP patients receiving eltrombopag therapy. The expansion of peripheral monocytes positively correlated with IFN-γ/IL-4 ratio in ITP patients. ITP macrophages exhibited more M1-related characteristics. After eltrombopag therapy, the peripheral monocyte count and IFN-γ/IL-4 ratio significantly decreased in ITP patients. M1-related characteristics of ITP macrophages were partially reversed by eltrombopag. What is the impact? This study provides evidence that the potential vital roles of TPO-RAs in regulating the monocyte/macrophage plasticity in ITP.