Inserm U970, Paris Cardiovascular Research Center, Paris, France; Université René Descartes, Paris, France.
Luxembourg Institute of Health, Department of Infection and Immunity, Strassen, Luxembourg.
J Am Coll Cardiol. 2018 Jan 16;71(2):160-172. doi: 10.1016/j.jacc.2017.10.084.
Several epidermal growth factor receptor (EGFR) inhibitors have been successfully developed for the treatment of cancer, limiting tumor growth and metastasis. EGFR is also expressed by leukocytes, but little is known about its role in the modulation of the immune response.
The aim of this study was to determine whether EGFR expressed on CD4 T cells is functional and to address the consequences of EGFR inhibition in atherosclerosis, a T cell-mediated vascular chronic inflammatory disease.
The authors used EGFR tyrosine kinase inhibitors (AG-1478, erlotinib) and chimeric LdlrCd4-Cre/Egfr mouse with a specific deletion of EGFR in CD4 T cells.
Mouse CD4 T cells expressed EGFR, and the EGFR tyrosine kinase inhibitor AG-1478 blocked in vitro T cell proliferation and Th1/Th2 cytokine production. In vivo, treatment of Ldlr mice with the EGFR inhibitor erlotinib induced T cell anergy, reduced T cell infiltration within atherosclerotic lesions, and protected against atherosclerosis development and progression. Selective deletion of EGFR in CD4 T cells resulted in decreased T cell proliferation and activation both in vitro and in vivo, as well as reduced interferon-γ, interleukin-4, and interleukin-2 production. Atherosclerotic lesion size was reduced by 2-fold in irradiated Ldlr mice reconstituted with bone marrow from Cd4-Cre/Egfr mice, compared to Cd4-Cre/Egfr chimeric mice, after 4, 6, and 12 weeks of high-fat diet, associated with marked reduction in T cell infiltration in atherosclerotic plaques. Human blood T cells expressed EGFR and EGFR inhibition reduced T cell proliferation both in vitro and in vivo.
EGFR blockade induced T cell anergy in vitro and in vivo and reduced atherosclerosis development. Targeting EGFR may be a novel strategy to combat atherosclerosis.
已有几种表皮生长因子受体 (EGFR) 抑制剂成功开发用于癌症治疗，限制了肿瘤的生长和转移。EGFR 也在白细胞中表达，但对于其在免疫反应调节中的作用知之甚少。
本研究旨在确定 CD4 T 细胞上表达的 EGFR 是否具有功能，并探讨 EGFR 抑制在动脉粥样硬化（一种 T 细胞介导的血管慢性炎症性疾病）中的后果。
作者使用 EGFR 酪氨酸激酶抑制剂 (AG-1478、厄洛替尼) 和在 CD4 T 细胞中特异性缺失 EGFR 的嵌合 LdlrCd4-Cre/Egfr 小鼠。
小鼠 CD4 T 细胞表达 EGFR，EGFR 酪氨酸激酶抑制剂 AG-1478 阻断体外 T 细胞增殖和 Th1/Th2 细胞因子产生。在体内，用 EGFR 抑制剂厄洛替尼治疗 LDLR 小鼠诱导 T 细胞失能，减少动脉粥样硬化病变内的 T 细胞浸润，并预防动脉粥样硬化的发展和进展。CD4 T 细胞中 EGFR 的选择性缺失导致体内外 T 细胞增殖和活化减少，以及干扰素-γ、白细胞介素-4 和白细胞介素-2 产生减少。与嵌合小鼠相比，用 CD4-Cre/Egfr 小鼠的骨髓重建的照射 LDLR 小鼠，在高脂肪饮食 4、6 和 12 周后，动脉粥样硬化病变大小减少了 2 倍，与动脉粥样硬化斑块中 T 细胞浸润的显著减少相关。人血 T 细胞表达 EGFR，EGFR 抑制减少体内外 T 细胞增殖。
EGFR 阻断在体内和体外诱导 T 细胞失能，并减少动脉粥样硬化的发展。靶向 EGFR 可能是对抗动脉粥样硬化的一种新策略。
