Macrophage Cluster of Differentiation 163 promotes post-infarction cardiac repair and preserves left ventricular
Jingyu Chen1, Linjian Chen1, Wei Huang1
1Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, China.
Insights
Cluster of Differentiation 163 (CD163) plays a crucial role in cardiac repair after myocardial infarction (MI) by upregulating osteopontin (OPN). This finding offers new therapeutic targets for ischaemic cardiomyopathy (ICM).
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Cardiac macrophages (cMacs) are vital for myocardial repair post-myocardial infarction (MI).
- The therapeutic potential of cMacs in ischaemic cardiomyopathy (ICM) is hindered by a lack of understanding of their molecular regulation.
- Cluster of Differentiation 163 (CD163), highly expressed in cMacs, has an unknown role in post-MI cardiac repair.
Purpose of the Study:
- To investigate the association between soluble CD163 and heart failure in ICM patients.
- To elucidate the functional role of CD163 in cardiac repair following MI.
- To explore the therapeutic potential of CD163 and osteopontin (OPN) in ICM.
Main Methods:
- Clinical study assessing soluble CD163 levels in ICM patients.
- Murine model of MI using wild-type and Cd163-deficient mice.
- Single-cell RNA sequencing for immune cell transcriptional analysis.
- Administration of recombinant CD163 and OPN to assess therapeutic effects.
Main Results:
- Elevated soluble CD163 levels in ICM patients correlated with heart failure severity and left ventricular (LV) dysfunction.
- Cd163-deficient mice exhibited exacerbated LV systolic dysfunction, reduced cardiac function, and impaired myocardial strain post-MI.
- Recombinant CD163 and OPN administration reversed systolic dysfunction, reduced LV dilation, and improved cardiac structure in deficient mice.
Conclusions:
- CD163 in cMacs promotes post-MI repair by upregulating OPN expression, crucial for maintaining systolic function.
- Soluble CD163 serves as a potential biomarker for ICM and LV dysfunction.
- Targeting CD163 and OPN pathways presents a promising therapeutic strategy for ICM.
Background:
Cardiac macrophages (cMacs) have been implicated in myocardial repair following myocardial infarction (MI), yet their therapeutic potential in ischaemic cardiomyopathy (ICM) remains limited by an incomplete understanding of their molecular regulation. Cluster of Differentiation 163 (CD163) is highly expressed in these macrophages, yet its functional role in regulating post-MI cardiac repair remains unknown.
Methods:
A cross-sectional clinical study was conducted to assess the association between circulating soluble CD163 concentration and heart failure due to ICM. To investigate the functional contribution of CD163 in ICM, wild-type (WT) and Cd163- / - mice were subjected to permanent ligation of the left anterior descending coronary artery. Single-cell RNA sequencing was employed to analyse transcriptional changes in cardiac immune cells. Recombinant osteopontin (OPN) and CD163 were administered to assess their therapeutic effect in Cd163- / - mice.
Results:
Circulating soluble CD163 levels were markedly elevated in patients with ICM-induced heart failure compared with individuals without heart failure (median difference 34.5 ng/mL, IQR 13.6-54.6 ng/mL, p = .002) and showed a positive correlation with the extent of systolic dysfunction and left ventricular (LV) dilation. Cd163- / - mice displayed aggravated LV systolic dysfunction, reduced ejection fraction and fractional shortening, impaired myocardial strain and reduced relative wall thickness post-MI. Recombinant CD163 protein could reverse systolic dysfunction and LV dilation in Cd163- / - mice after MI. CD163 was predominantly expressed in CCR2- resident cMacs, and CD163 deficiency altered transcriptional programmes of macrophages without affecting their polarization status, with enrichment in cytokine signalling and extracellular matrix-related pathways. Spp1 (OPN) expression was significantly downregulated in Cd163- / - hearts under both sham and MI conditions. Administration of recombinant OPN improved systolic function, reduced ventricular dilation, decreased fibrotic scar size and restored the elastin-to-collagen ratio in Cd163- / - mice.
Conclusions:
In cMacs, CD163 contributes to post-MI repair by upregulating OPN expression, which in turn helps maintain systolic function.
Key Points:
Soluble CD163 is elevated in ICM and correlates with LV dysfunction. Cd163- / - mice show worsened post-MI systolic dysfunction and dilation. Recombinant CD163 reverses dysfunction in Cd163- / - mice. OPN restores function and improves LV structure in Cd163- / - mice.
