Monocyte-endothelial interactions as a targetable node in clonal hematopoiesis-mediated cardiovascular disease

Area of Science:

• Cardiovascular Biology
• Hematology
• Immunology

Background:

• Clonal hematopoiesis of indeterminate potential (CHIP) is linked to increased cardiovascular disease (CVD) risk.
• The precise molecular mechanisms underlying CHIP-associated CVD remain unclear.
• Aberrant monocyte-endothelial cell interactions are hypothesized to mediate CHIP's contribution to CVD.

Purpose of the Study:

• To investigate the role of monocyte-endothelial cell interactions in CHIP-mediated CVD.
• To identify molecular targets that can restore normal monocyte-endothelial cell function in CHIP.

Main Methods:

• Single-cell RNA sequencing was performed on monocytes and endothelial cells from CHIP patients (TET2, DNMT3A) and controls.
• Ligand-receptor interactions were predicted, and monocyte-endothelial cell co-cultures were established.
• An in silico perturbation screen identified potential therapeutic targets, followed by in vitro experimental validation.

Main Results:

• CHIP mutations altered ligand-receptor expression, impacting signaling pathways related to transendothelial migration.
• Monocytes with CHIP mutations exhibited reduced velocity when interacting with endothelial cells.
• Inhibition of ICAM1 (endothelial cells) and CXCR2 (monocytes) significantly improved the velocity of TET2 CHIP monocytes.

Conclusions:

• CHIP mutations disrupt normal monocyte-endothelial cell interactions.
• Targeting CXCR2 and ICAM1 presents a potential therapeutic strategy to normalize these interactions in TET2 CHIP, potentially mitigating CVD risk.