Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.
Department of Biomedical Sciences, Laboratory of Immunology and Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
Immun Inflamm Dis. 2021 Sep;9(3):871-882. doi: 10.1002/iid3.442. Epub 2021 May 4.
Transglutaminase 2 (TG2), a multifunctional calcium-dependent acyltransferase, is upregulated in asthmatic airways and reported to play a role in the pathogenesis of allergic asthma. However, the underlying mechanism is not fully understood.
To investigate the role of TG2 in alternative activation of alveolar macrophages by using murine asthma model.
TG2 expression was assessed in induced sputum of 21 asthma patients and 19 healthy controls, and lung tissue of ovalbumin (OVA)-induced murine asthma model. To evaluate the role of TG2 in asthma, we developed an OVA asthma model in both TG2 null and wild-type mice. The expression of M2 macrophage markers was measured by fluorescence-activated cell sorting (FACS) after OVA sensitization and challenge. To evaluate the effect of TG2 inhibition in vitro, interleukin 4 (IL-4) or IL-13-stimulated expression of M2 macrophage markers was measured in CRL-2456 cells in the presence and absence of a TG2 inhibitor.
The expression of both TG2 and M2 markers was increased in the sputum of asthmatics compared with that of healthy controls. The expression of TG2 was increased in macrophages of OVA mice. Airway hyperresponsiveness, and the number of inflammatory cells, including eosinophils, was significantly reduced in TG2 null mice compared with wild-type mice. Enhanced expression of M2 markers in OVA mice was normalized by TG2 knockout. IL-4 or IL-13-stimulated expression of M2 markers in alveolar macrophages was also attenuated by TG2 inhibitor treatment in vitro.
Our results suggest that TG2-mediated modulation of alveolar macrophage polarization plays important roles in the pathogenesis of asthma.
转谷氨酰胺酶 2（TG2）是一种多功能的钙依赖性酰基转移酶，在哮喘气道中上调，并被报道在变应性哮喘的发病机制中发挥作用。然而，其潜在机制尚不完全清楚。
通过使用小鼠哮喘模型研究 TG2 在肺泡巨噬细胞替代激活中的作用。
评估 21 例哮喘患者和 19 例健康对照者诱导痰中 TG2 的表达以及卵清蛋白（OVA）诱导的小鼠哮喘模型肺组织中 TG2 的表达。为了评估 TG2 在哮喘中的作用，我们在 TG2 缺失和野生型小鼠中建立了 OVA 哮喘模型。OVA 致敏和激发后，通过荧光激活细胞分选（FACS）测量 M2 巨噬细胞标志物的表达。为了评估体外 TG2 抑制的效果，在存在和不存在 TG2 抑制剂的情况下，测量 CRL-2456 细胞中白细胞介素 4（IL-4）或白细胞介素 13（IL-13）刺激的 M2 巨噬细胞标志物的表达。
与健康对照组相比，哮喘患者的痰中 TG2 和 M2 标志物的表达均增加。OVA 小鼠的巨噬细胞中 TG2 的表达增加。与野生型小鼠相比，TG2 缺失小鼠的气道高反应性以及包括嗜酸性粒细胞在内的炎症细胞数量明显减少。在 TG2 敲除小鼠中，OVA 小鼠增强的 M2 标志物表达得到了正常化。体外 TG2 抑制剂处理也减弱了 IL-4 或 IL-13 刺激的肺泡巨噬细胞中 M2 标志物的表达。
我们的结果表明，TG2 介导的肺泡巨噬细胞极化调节在哮喘发病机制中发挥重要作用。
