IFN-γ-STAT1-ERK Pathway Mediates Protective Effects of Invariant Natural Killer T Cells Against Doxorubicin-Induced Cardiomyocyte Death

Masashi Sada; Shouji Matsushima; Masataka Ikeda; Soichiro Ikeda; Kosuke Okabe; Akihito Ishikita; Tomonori Tadokoro; Nobuyuki Enzan; Taishi Yamamoto; Hiroko Deguchi Miyamoto; Yoshitomo Tsutsui; Ryo Miyake; Daiki Setoyama; Dongchon Kang; Tomomi Ide; Hiroyuki Tsutsui

doi:10.1016/j.jacbts.2023.02.014

IFN-γ-STAT1-ERK Pathway Mediates Protective Effects of Invariant Natural Killer T Cells Against Doxorubicin-Induced Cardiomyocyte Death

JACC Basic Transl Sci. 2023 Jun 21;8(8):992-1007. doi: 10.1016/j.jacbts.2023.02.014. eCollection 2023 Aug.

Authors

Masashi Sada^{1

2}, Shouji Matsushima^{1

2}, Masataka Ikeda^{1

2}, Soichiro Ikeda^{1

2}, Kosuke Okabe^{1

2}, Akihito Ishikita^{1

2}, Tomonori Tadokoro^{1

2}, Nobuyuki Enzan^{1

2}, Taishi Yamamoto^{1

2}, Hiroko Deguchi Miyamoto^{1

2}, Yoshitomo Tsutsui^{1

2}, Ryo Miyake^{1

2}, Daiki Setoyama³, Dongchon Kang³, Tomomi Ide¹, Hiroyuki Tsutsui^{1

2}

Affiliations

¹ Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Abstract

Doxorubicin (DOX)-induced cardiomyopathy has poor prognosis, and myocardial inflammation is intimately involved in its pathophysiology. The role of invariant natural killer T (iNKT) cells has not been fully determined in this disease. We here demonstrated that activation of iNKT cells by α-galactosylceramide (GC) attenuated DOX-induced cardiomyocyte death and cardiac dysfunction. αGC increased interferon (IFN)-γ and phosphorylation of signal transducers and activators of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK). Administration of anti-IFN-γ neutralizing antibody abrogated the beneficial effects of αGC on DOX-induced cardiac dysfunction. These findings emphasize the protective role of iNKT cells in DOX-induced cardiomyopathy via the IFN-γ-STAT1-ERK pathway.

Keywords: apoptosis; cardiomyopathy; doxorubicin; interferon-gamma; natural killer T cells.