Related Experiment Video
Updated: Aug 11, 2025
Isolation and Identification of Extravascular Immune Cells of the Heart
Published on: August 23, 2018
XCR1+ conventional dendritic cell-induced CD4+ T helper 1 cell activation exacerbates cardiac remodeling after
Hiroyasu Inui1, Makoto Nishida2, Michiko Ichii3
1Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Insights
Inflammation drives cardiac remodeling after heart injury. This study reveals that XCR1+ cDC1 cells activate CXCR3+ Th1 cells, worsening cardiac dysfunction. Depleting these cells protected the heart.
Area of Science:
- Immunology
- Cardiovascular Biology
- Inflammation Research
Background:
- Cardiac remodeling following ischemic injury lacks targeted anti-inflammatory therapies.
- CD4+ T-cell subsets are implicated in myocardial injury healing, but their activation pathways are unclear.
Purpose of the Study:
- To investigate immune reactions in cardiac remodeling using a high-fat diet-induced coronary heart disease (HFD-CHD) mouse model.
- To determine if probucol, an anti-inflammatory agent, can suppress cardiac remodeling in HFD-CHD mice.
- To elucidate the roles of T helper 1 (Th1) cells and dendritic cells (cDC1) in ischemic cardiac remodeling.
Main Methods:
- Utilized a high-fat diet-induced coronary heart disease (HFD-CHD) mouse model and a coronary artery ligation-induced myocardial infarction (ligation-MI) model.
- Employed flow cytometry to analyze immune cell populations (CD4+ Th1, XCR1+ cDC1) and RNA sequencing (RNA-seq) to assess gene expression (CXCR3).
- Investigated the therapeutic effect of probucol and performed cell depletion studies (XCR1+ cDC1) in vivo.
Main Results:
- HFD-CHD mice exhibited predominant CD4+ T Helper 1 (Th1) cell activation and cardiac dysfunction.
- Probucol treatment reduced cardiac dysfunction and Th1 cell activation in HFD-CHD mice, suppressing CXCR3 expression.
- XCR1+ cDC1 cells, expressing CXCR3 ligands, were activated in HFD-CHD and ligation-MI models; their depletion prevented cardiac dysfunction post-MI.
- XCR1+ cDC1 and CXCR3+ Th1 cells were found in human cardiac infarcts.
Conclusions:
- Identified a novel pathway where XCR1+ cDC1 cells activate CXCR3+ Th1 cells, contributing critically to ischemic cardiac remodeling.
- Suggests targeting the XCR1+ cDC1-CXCR3+ Th1 axis as a potential therapeutic strategy for cardiac remodeling.
Abstract:
Cardiac remodeling has no established therapies targeting inflammation. CD4+ T-cell subsets have been reported to play significant roles in healing process after ischemic myocardial injury, but their detailed mechanisms of activation remain unknown. To explore immune reactions during cardiac remodeling, we applied a non-surgical model of coronary heart disease (CHD) induced by a high-fat diet (HFD-CHD) in SR-BI-/-/ApoeR61h/h mice. Flow cytometry analyses throughout the period of progressive cardiac dysfunction revealed that CD4+ T Helper 1 (Th1) cells were predominantly activated in T-cell subsets. Probucol was reported to attenuate cardiac dysfunction after coronary artery ligation model (ligation-MI) in rats. To determine whether probucol suppress cardiac remodeling after HFD-CHD, we treated SR-BI-/-/ApoeR61h/h mice with probucol. We found treatment with probucol in HFD-CHD mice reduced cardiac dysfunction, with attenuated activation of Th1 cells. RNA-seq analyses revealed that probucol suppressed the expression of CXCR3, a Th1-related chemokine receptor, in the heart. XCR1+ cDC1 cells, which highly expresses the CXCR3 ligands CXCL9 and CXCL10, were predominantly activated after HFD-CHD. XCR1+ cDC1 lineage skewing of pre-DC progenitors was observed in bone marrow, with subsequent systemic expansion of XCR1+ cDC1 cells after HFD-CHD. Activation of CXCR3+ Th1 cell and XCR1+ cDC1 cells was also observed in ligation-MI. Notably, post-MI depletion of XCR1+ cDC1 cells suppressed CXCR3+ Th1 cell activation and prevented cardiac dysfunction. In patient autopsy samples, CXCR3+ Th1 and XCR1+ cDC1 cells infiltrated the infarcted area. In this study, we identified a critical role of XCR1+ cDC1-activated CXCR3+ Th1 cells in ischemic cardiac remodeling.
