α-Galactosylceramide and its analog OCH differentially affect the pathogenesis of ISO-induced cardiac injury in mice

Xin Chen1, Jie Liu1, Wen-jia Wang1, Wen-jing Lai2, Shu-hui Li3, Ya-fei Deng4, Jian-zhi Zhou5, Sheng-qian Yang1, Ying Liu6, Wei-nian Shou6, Da-yan Cao1, Xiao-hui Li1
1 Institute of Materia Medica and Center of Translational Medicine, College of Pharmacy, Army Medical University, Chongqing 400038, China
2 Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
3 Department of Clinical Biochemistry, College of Pharmacy, Army Medical University, Chongqing 400038, China
4 Hunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha 410007, China
5 School of Medicine, Chongqing University, Chongqing 400016, China
6 Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
Correspondence to: Da-yan Cao:, Xiao-hui Li:,
DOI: 10.1038/s41401-020-00517-z
Received: 13 May 2020
Accepted: 13 August 2020
Advance online: 24 September 2020


Immunotherapies for cancers may cause severe and life-threatening cardiotoxicities. The underlying mechanisms are complex and largely elusive. Currently, there are several ongoing clinical trials based on the use of activated invariant natural killer T (iNKT) cells. The potential cardiotoxicity commonly associated with this particular immunotherapy has yet been carefully evaluated. The present study aims to determine the effect of activated iNKT cells on normal and β-adrenergic agonist (isoproterenol, ISO)-stimulated hearts. Mice were treated with iNKT stimulants, α-galactosylceramide (αGC) or its analog OCH, respectively, to determine their effect on ISO-induced cardiac injury. We showed that administration of αGC (activating both T helper type 1 (Th1)- and T helper type 2 (Th2)-liked iNKT cells) significantly accelerated the progressive cardiac injury, leading to enhanced cardiac hypertrophy and cardiac fibrosis with prominent increases in collagen deposition and TGF-β1, IL-6, and alpha smooth muscle actin expression. In contrast to αGC, OCH (mainly activating Th2-liked iNKT cells) significantly attenuated the progression of cardiac injury and cardiac inflammation induced by repeated infusion of ISO. Flow cytometry analysis revealed that αGC promoted inflammatory macrophage infiltration in the heart, while OCH was able to restrain the infiltration. In vitro coculture of αGC- or OCH-pretreated primary peritoneal macrophages with primary cardiac fibroblasts confirmed the profibrotic effect of αGC and the antifibrotic effect of OCH. Our results demonstrate that activating both Th1- and Th2-liked iNKT cells is cardiotoxic, while activating Th2-liked iNKT cells is likely cardiac protective, which has implied key differences among subpopulations of iNKT cells in their response to cardiac pathological stimulation.
Keywords: α-galactosylceramide; OCH; iNKT cells; isoproterenol; cancer immunotherapy; cardiotoxicity; oncocardiology

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