Vitamin D receptor restricts T helper 2-biased inflammation in the heart.

Abstract

Background and aims:

The aberrant immune responses play a critical role in the pathogenesis of myocarditis. Vitamin D receptor (VDR) has immune regulatory functions. This study aims to investigate the role of VDR in restricting the immune inflammation in the heart.

Methods and results:

The human heart samples were obtained from the heart transplantation. T helper (Th)2 and Th1 responses in the heart tissue were characterized by histology and immune assay. VDR-/- mice and recombination activating gene 2-/- mice were used in the experiments to test the role of VDR in maintaining the homeostasis in the heart. The results showed that, besides tissue damage, lower expression of VDR, high frequency of Th2 cells and increase in Th2 cytokines in the hearts of patients with myocarditis at the end stage of heart failure. The spontaneous Th2-biased inflammation was observed in the hearts of VDR-/- mice. CD4+ T cells from the VDR-/- mouse hearts were at highly activating status. The naïve VDR-/- CD4+ T cells and naïve CD4+ T cells from human hearts with myocarditis were prone to differentiate into Th2 cells. VDR formed complexes with GATA3, the interleukin (IL)-4 transcription factor, to prevent the Il4 gene transcription. Transplantation with VDR-/-CD4+ T cells induced the Th2-biased inflammation in the hearts of Rag2-/- mice. Reconstitution of VDR in CD4+ T cells inhibited the Th2-biased inflammation in the heart.

Conclusions:

VDR-deficiency contributes to the pathogenesis of myocarditis. To enhance the VDR expression in CD4+, T cells haves the therapeutic potential for the treatment of myocarditis.

• Authors: Jiangping Song, Xiao Chen, Liang Cheng, Man Rao, Kai Chen, Ningning Zhang, Jian Meng, Mengmeng Li, Zhi-Qiang Liu, Ping-Chang Yang
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 114 Issue 6 Pg. 870-879 (05 01 2018) ISSN: 1755-3245 [Electronic] England
• PMID: 29444238 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• DNA-Binding Proteins
• GATA3 Transcription Factor
• Gata3 protein, mouse
• Il4 protein, mouse
• Inflammation Mediators
• Rag2 protein, mouse
• Receptors, Calcitriol
• VDR protein, human
• Interleukin-4

Topics

• Adoptive Transfer
• Adult
• Animals
• Cell Differentiation
• Cells, Cultured
• Cytokines (genetics, immunology, metabolism)
• DNA-Binding Proteins (deficiency, genetics)
• Disease Models, Animal
• Female
• GATA3 Transcription Factor (genetics, immunology, metabolism)
• Genetic Predisposition to Disease
• Humans
• Inflammation Mediators (metabolism)
• Interleukin-4 (genetics, immunology, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Myocarditis (genetics, immunology, metabolism, prevention & control)
• Myocytes, Cardiac (immunology, metabolism, pathology)
• Phenotype
• Receptors, Calcitriol (genetics, immunology, metabolism)
• Signal Transduction
• Th2 Cells (immunology, metabolism, transplantation)
• Young Adult