Lynda Zeboudj1, Mikael Maître1, Lea Guyonnet1, Ludivine Laurans1, Jeremie Joffre1, Jeremie Lemarie1, Simon Bourcier1, Wared Nour-Eldine1, Coralie Guérin2, Jonas Friard3, Abdelilah Wakkach3, Elizabeth Fabre4, Alain Tedgui1, Ziad Mallat5, Pierre-Louis Tharaux1, Hafid Ait-Oufella6. 1. Inserm U970, Paris Cardiovascular Research Center, Paris, France; Université René Descartes, Paris, France. 2. Luxembourg Institute of Health, Department of Infection and Immunity, Strassen, Luxembourg. 3. CNRS, LP2M, UMR 7370, Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France. 4. Department of Medical Oncology, Hôpital Europeen G. Pompidou, AP-HP, Paris, France. 5. Inserm U970, Paris Cardiovascular Research Center, Paris, France; Université René Descartes, Paris, France; Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom. 6. Inserm U970, Paris Cardiovascular Research Center, Paris, France; Université René Descartes, Paris, France; Service de Réanimation Médicale, Hôpital Saint-Antoine, AP-HP, Université Pierre-et-Marie Curie, Paris, France. Electronic address: hafid.aitoufella@inserm.fr.
Abstract
BACKGROUND: 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. OBJECTIVES: 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. METHODS: The authors used EGFR tyrosine kinase inhibitors (AG-1478, erlotinib) and chimeric Ldlr-/-Cd4-Cre/Egfrlox/lox mouse with a specific deletion of EGFR in CD4+ T cells. RESULTS: 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/Egfrlox/lox 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. CONCLUSIONS: 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.
BACKGROUND: 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. OBJECTIVES: 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. METHODS: The authors used EGFR tyrosine kinase inhibitors (AG-1478, erlotinib) and chimeric Ldlr-/-Cd4-Cre/Egfrlox/lox mouse with a specific deletion of EGFR in CD4+ T cells. RESULTS: 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/Egfrlox/lox 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. CONCLUSIONS: 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.
Authors: Lars Brodowski; Tristan Zindler; Sandra von Hardenberg; Bianca Schröder-Heurich; Constantin S von Kaisenberg; Helge Frieling; Carl A Hubel; Thilo Dörk; Frauke von Versen-Höynck Journal: Front Cell Dev Biol Date: 2019-03-19