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

Abstract

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.

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Fig. 1: Effects of long-term αGC treatment on cardiac morphology and function.
Fig. 2: iNKT cells activated by αGC accelerate progressive ISO stimulation-induced cardiac fibrosis in mice.
Fig. 3: Cytokine expression patterns after administration of ISO (5 mg/kg per day) alone for 7 days or with αGC (3 μg/mouse) every other day.
Fig. 4: iNKT cells activated by OCH attenuate progressive ISO stimulation-induced cardiac fibrosis in mice.
Fig. 5: Cytokine expression patterns after administration of ISO (5 mg/kg per day) alone for 7 days or with OCH (3 μg/mouse) every other day.
Fig. 6: αGC and OCH differentially regulate the pathogenesis of cardiac injury induced by a single dose of ISO.
Fig. 7: αGC-induced acceleration of progressive ISO stimulation-induced cardiac fibrosis was partly reversed by an IL-6 neutralizing antibody.
Fig. 8: Cardiac macrophages in αGC-induced cardiotoxicity.
Fig. 9: The effect of iNKT cell activation on naive fibroblast cells.

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (#81773742 and #81520108029 to XHL, #81703521 to YFD, and #81473260 to JZZ).

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XHL, and DYC, designed research; XC, JL, JL, WJW, YFD, SQY, and WJL, performed research; XC, SHL, YL, and DYC, analyzed data; XC, and DYC, drafted the paper; DYC, WNS, JZZ, and XHL, revised and finalized the paper. All authors contributed to and have approved the paper.

Corresponding authors

Correspondence to Da-yan Cao or Xiao-hui Li.

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Chen, X., Liu, J., Liu, J. et al. α-Galactosylceramide and its analog OCH differentially affect the pathogenesis of ISO-induced cardiac injury in mice. Acta Pharmacol Sin 41, 1416–1426 (2020). https://doi.org/10.1038/s41401-020-00517-z

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Keywords

  • α-galactosylceramide
  • OCH
  • iNKT cells
  • isoproterenol
  • cancer immunotherapy
  • cardiotoxicity
  • oncocardiology

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